JP2012514019A - Toluidinesulfonamides and their use as inhibitors - Google Patents
Toluidinesulfonamides and their use as inhibitors Download PDFInfo
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Abstract
本発明は、細胞増殖及び細胞分裂を阻害し、低酸素条件下において低酸素誘導因子(HIF)に媒介される転写及びシグナル伝達の活性化を阻害する、式(I)の化合物(式中、R1は単環式の5員又は6員のヘテロアリールであり、R4はフェニル、又は単環式の5員若しくは6員のヘテロアリールであり、他の置換基は特許請求の範囲において規定される通りである)を提供する。一態様では、本発明の化合物は、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び過剰な血管新生を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防のための薬物の調製に有用である。本発明の化合物、及び言及される疾患又は障害の治療又は予防に有用な第2の治療薬又は放射線を含む、医薬組成物も提供される。
【選択図】なしThe present invention relates to compounds of formula (I) that inhibit cell proliferation and cell division and inhibit activation of transcription and signaling mediated by hypoxia-inducible factor (HIF) under hypoxic conditions, wherein R 1 is a monocyclic 5- or 6-membered heteroaryl, R 4 is phenyl, or a monocyclic 5- or 6-membered heteroaryl, and other substituents are defined in the claims. As is). In one aspect, the compound of the invention comprises a disease or disorder selected from the group consisting of inflammatory diseases, hyperproliferative diseases or hyperproliferative disorders, hypoxia-related lesions, and diseases characterized by excessive angiogenesis. Useful for the preparation of drugs for treatment or prevention. Also provided are pharmaceutical compositions comprising a compound of the invention and a second therapeutic agent or radiation useful for the treatment or prevention of the disease or disorder referred to.
[Selection figure] None
Description
本発明は、細胞増殖及び細胞分裂を阻害し、低酸素条件下において低酸素誘導因子(HIF)に媒介される転写及びシグナル伝達の活性化を阻害する、新規な化合物を提供する。一態様では、本発明の化合物は、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び過剰な血管新生を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防のための薬物の調製に有用である。本発明の化合物、及び言及される疾患又は障害の治療又は予防に有用な第2の治療薬又は放射線を含む、医薬組成物も提供される。 The present invention provides novel compounds that inhibit cell proliferation and cell division and inhibit activation of transcription and signaling mediated by hypoxia-inducible factor (HIF) under hypoxic conditions. In one aspect, the compound of the invention comprises a disease or disorder selected from the group consisting of inflammatory diseases, hyperproliferative diseases or hyperproliferative disorders, hypoxia-related lesions, and diseases characterized by excessive angiogenesis. Useful for the preparation of drugs for treatment or prevention. Also provided are pharmaceutical compositions comprising a compound of the invention and a second therapeutic agent or radiation useful for the treatment or prevention of the disease or disorder referred to.
不十分な酸素供給に対する細胞の正常な応答は、低酸素シグナル伝達経路により媒介される。この応答は、多数の生理学的(physiolocial)機能、例えば腫瘍の発生及び転移、アポトーシスに対する抵抗性、新たな血管の形成の誘導、並びに代謝等にとって重要である。低酸素シグナル伝達に関する包括的な概説に関しては、例えば非特許文献1を参照されたい。 The normal response of cells to inadequate oxygen supply is mediated by the hypoxic signaling pathway. This response is important for many physiological functions such as tumor development and metastasis, resistance to apoptosis, induction of new blood vessel formation, and metabolism. See, for example, Non-Patent Document 1 for a comprehensive review on hypoxic signaling.
低酸素の結果として、例えば腫瘍において、この高速で成長する組織の種類における酸素及び栄養素の可用性の低減を付加的な補因子と協働して補うための、転写因子(低酸素誘導因子、HIF)、中でもHIF−1α及びHIF−1βのヘテロ二量体の複合体のレベルの増大が、観察される。嫌気条件下では、HIF−1αの恒常性はその分解の低減により不均衡なものとなっているため、低酸素応答要素(HRE)を介するシグナル伝達の増強が可能となり、多数の生存因子及び成長因子の発現の増大をもたらす。 As a result of hypoxia, for example, in tumors, transcription factors (hypoxia-inducing factor, HIF) to supplement the reduced availability of oxygen and nutrients in this rapidly growing tissue type in conjunction with additional cofactors. ), Among others, increased levels of HIF-1α and HIF-1β heterodimeric complexes are observed. Under anaerobic conditions, HIF-1α homeostasis is unbalanced due to its reduced degradation, allowing for enhanced signaling through the hypoxia responsive element (HRE), a number of survival factors and growth This leads to increased expression of the factor.
低酸素の病態は、非腫瘍組織にも見出される。例えば、網膜症は、目の網膜に対する非炎症性の損傷を表す一般的な用語である。この病態は、低酸素状態をもたらす不十分な血液供給により引き起こされることが最も一般的である。特に、糖尿病の人は、網膜症のリスクを有する。糖尿病患者の網膜における酸素の欠乏は、脆い新生血管を、網膜に沿ってまた目の内側を充たす透明なゲル様の硝子体液中において成長させる。適時な治療を行わぬ場合、これらの新たな血管は、出血し、視界を曇らせ、網膜を破壊する可能性がある。線維血管性の増殖も、部分的な網膜剥離を引き起こすことがある。新たな血管が、目の前房中まで成長し、血管新生緑内障を引き起こすこともある。 Hypoxic conditions are also found in non-tumor tissues. For example, retinopathy is a general term for non-inflammatory damage to the retina of the eye. This condition is most commonly caused by an inadequate blood supply that results in hypoxia. In particular, people with diabetes are at risk for retinopathy. Oxygen deficiency in the retina of diabetics causes fragile new blood vessels to grow in clear gel-like vitreous humor along the retina and inside the eye. Without timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. Fibrovascular proliferation can also cause partial retinal detachment. New blood vessels can grow into the anterior chamber of the eye and cause neovascular glaucoma.
近年、HIF−1活性の阻害が、マクロファージ及び好中球の活性化及び罹患組織中への浸潤におけるその役割に基づき、炎症を予防するように作用する可能性もあることの証拠が、集まってきている(例えば非特許文献2を参照されたい)。 In recent years, evidence has gathered that inhibition of HIF-1 activity may act to prevent inflammation based on its role in macrophage and neutrophil activation and infiltration into diseased tissues. (For example, see Non-Patent Document 2).
上で概説した理由のために、HIFの機能を阻害する化合物は、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び過剰な血管新生を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防のための価値のある薬物である。 For the reasons outlined above, the compound that inhibits the function of HIF comprises the group consisting of inflammatory diseases, hyperproliferative or hyperproliferative disorders, hypoxia-related lesions, and diseases characterized by excessive angiogenesis A valuable drug for the treatment or prevention of a disease or disorder selected from:
腫瘍の発生、進行及び転移におけるHIF−1の重要性のために、がん療法のためのHIF−1阻害剤を同定するためにかなりの量の労力が費やされている。多数の小分子及びRNA構築物、例えばsiRNAが、HIF−1経路の阻害を示すことが報告されている(例えば非特許文献3、非特許文献4、非特許文献5、非特許文献6、非特許文献7、非特許文献8、非特許文献9、非特許文献10)。しかしながら、これらの化合物はHIF−1阻害以外の活性を有することが多く、それらのほとんどは、有用な医薬品に必要とされる所望の薬物動態特性又は毒性プロファイルを欠く。さらに、該化合物の幾つかは、ロックド核酸アンチセンスオリゴヌクレオチドであるHIF−1阻害剤EZN−2968のように、経口投与することができないという欠点を有する。 Because of the importance of HIF-1 in tumor development, progression and metastasis, a considerable amount of effort is expended to identify HIF-1 inhibitors for cancer therapy. Numerous small molecules and RNA constructs, such as siRNA, have been reported to exhibit inhibition of the HIF-1 pathway (eg, Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6, Non-patent). Document 7, Non-patent document 8, Non-patent document 9, Non-patent document 10). However, these compounds often have activities other than HIF-1 inhibition, and most of them lack the desired pharmacokinetic properties or toxicity profile required for useful pharmaceuticals. Furthermore, some of the compounds have the disadvantage that they cannot be administered orally, like the HIF-1 inhibitor EZN-2968, which is a locked nucleic acid antisense oligonucleotide.
上で引用した科学文献により、種々の増殖性及び炎症性の疾患又は障害、低酸素関連病変、並びに過剰な血管新生を特徴とする疾患のより効率的な治療をもたらす新たな治療薬に対する医療上の必要性が高いことが強調される。 The scientific literature cited above provides medical treatment for new therapeutic agents that provide more efficient treatment of various proliferative and inflammatory diseases or disorders, hypoxia-related lesions, and diseases characterized by excessive angiogenesis. It is emphasized that there is a high need for.
本発明は、疾患又は障害を予防又は治療することができる新規な化合物を提供する。本明細書において提示されるデータにより、本発明による化合物が、驚くべきことに、(i)低酸素条件下におけるHIFに媒介される転写の活性化の、及び(ii)細胞増殖の、非常に強力な阻害剤であることが確立される。 The present invention provides novel compounds that can prevent or treat diseases or disorders. The data presented herein show that the compounds according to the present invention are surprisingly (i) highly active in HIF-mediated transcription under hypoxic conditions and (ii) in cell proliferation. It is established to be a potent inhibitor.
第1の態様では、本発明は、式I: In a first aspect, the present invention provides compounds of formula I:
(式中、
R1は、単環式の5員又は6員のヘテロアリールであり、H、アルキル、アルケニル、アルキニル、−CN、ハロゲン、N−O(該窒素原子は該単環式の5員又は6員のヘテロアリールの一体部分(integral part)である)、−OH、アルコキシ、−SH、S−アルキル、−NH2、NH−アルキル、N−ビス−アルキル、NHOH、NMeOH、NMe(OMe)、−NO2、−CF3、−OCF3及びC1〜C4ヒドロキシアルキルからなる群から選択される1つ又は複数の置換基で任意に置換され、
R2はH又はC1〜C4アルキルであり、
R3はH又は−CH3であり、
R4は、フェニル、又は単環式の5員若しくは6員のヘテロアリールであり、アルキル、アルケニル、アルキニル、アルコキシ、ハロゲン、−CN、−CF3、−OCF3、C1〜C4ヒドロキシアルキル、−OH、−SH、S−アルキル、−CN、N−ビス−アルキル、シアノアセチレン、−NO2、−NR7R8、−C(O)R6、N−O(該窒素原子は該単環式の5員又は6員のヘテロアリールの一体部分である)、及び(R4がフェニルである場合)ジオキシメチレン架橋(−O−CH2−O−)を共に形成する2つの置換基からなる群から選択される1つ又は複数の置換基で任意に置換され、
R5はH又は−CH3であり、
R6はC1〜C4アルキルであり、
R7はH又はアルキルであり、
R8はH又はC1〜C4アルキルであり、
ただしR1は5−クロロ(choloro)−チオフェン−2−イルではなく、R5及びR3は同時にHではない)
による構造を有する化合物に関する。
(Where
R 1 is a monocyclic 5- or 6-membered heteroaryl, and H, alkyl, alkenyl, alkynyl, —CN, halogen, N—O (wherein the nitrogen atom is the monocyclic 5- or 6-membered) the integral part of the heteroaryl (integral part) is), - OH, alkoxy, -SH, S- alkyl, -NH 2, NH- alkyl, N- bis - alkyl, NHOH, NMeOH, NMe (OMe ), - NO 2, -CF 3, is optionally substituted with one or more substituents selected from the group consisting of -OCF 3, and C 1 -C 4 hydroxyalkyl,
R 2 is H or C 1 -C 4 alkyl;
R 3 is H or —CH 3 ;
R 4 is phenyl or monocyclic 5- or 6-membered heteroaryl, alkyl, alkenyl, alkynyl, alkoxy, halogen, —CN, —CF 3 , —OCF 3 , C 1 -C 4 hydroxyalkyl , —OH, —SH, S-alkyl, —CN, N-bis-alkyl, cyanoacetylene, —NO 2 , —NR 7 R 8 , —C (O) R 6 , N—O (the nitrogen atom is the Two substitutions that together form a dioxymethylene bridge (—O—CH 2 —O—) (when R 4 is phenyl), which is an integral part of a monocyclic 5- or 6-membered heteroaryl Optionally substituted with one or more substituents selected from the group consisting of groups,
R 5 is H or —CH 3 ;
R 6 is C 1 -C 4 alkyl;
R 7 is H or alkyl;
R 8 is H or C 1 -C 4 alkyl;
Where R 1 is not 5-chloro-thiophen-2-yl and R 5 and R 3 are not H at the same time)
To a compound having the structure
さらなる一態様では、本発明は、本発明による化合物又はその薬学的に許容可能な塩、並びに炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び病態生理学的な過剰血管新生(hyper-vascularisation)を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防に有用な第2の治療薬、並びに任意に薬学的に許容可能な担体又は賦形剤を含む、医薬組成物に関する。 In a further aspect, the present invention relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, as well as inflammatory diseases, hyperproliferative or hyperproliferative disorders, hypoxia-related lesions, and pathophysiological excess blood vessels. A second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of diseases characterized by hyper-vascularisation, and optionally a pharmaceutically acceptable carrier or excipient And to pharmaceutical compositions.
さらなる一態様では、本発明は、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び病態生理学的な過剰血管新生を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防のための薬物の調製のための、本発明による化合物又は本発明による組成物の使用に関する。 In a further aspect, the invention provides a disease selected from the group consisting of inflammatory diseases, hyperproliferative diseases or hyperproliferative disorders, hypoxia-related lesions, and diseases characterized by pathophysiological hyperangiogenesis or It relates to the use of a compound according to the invention or a composition according to the invention for the preparation of a medicament for the treatment or prevention of disorders.
別の態様では、本発明は、過剰増殖性疾患又は過剰増殖性障害を治療する方法であって、放射線療法、化学療法、免疫療法、レーザー/マイクロ波温熱療法、又はアンチセンスDNA及びRNAを使用する遺伝子療法を患者が受ける前に、受ける間に、及び/又は受けた後に、上記患者に対して本発明による化合物又は組成物を投与することを含む、方法を提供する。 In another aspect, the present invention is a method of treating a hyperproliferative disease or hyperproliferative disorder using radiation therapy, chemotherapy, immunotherapy, laser / microwave thermotherapy, or antisense DNA and RNA. A method is provided comprising administering to the patient a compound or composition according to the invention before, during and / or after receiving the gene therapy.
本明細書で使用される専門用語は、特定の実施形態を説明するためのものにすぎず、添付の特許請求の範囲によってのみ限定される本発明の範囲を限定することは意図されないことを理解すべきである。他に規定のない限り、本明細書で使用される全ての技術用語及び科学用語は、当業者により一般的に理解されるものと同じ意味を有する。 It is understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention which is limited only by the appended claims. Should. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
好ましくは、本明細書で使用される用語は、"Amultilingual glossary of biotechnological terms:(IUPACRecommendations)", Leuenberger, H. G. W, Nagel, B.and Klbl, H. eds.(1995),Helvetica Chimica Acta, CH-4010 Basel, Switzerland)で説明されているように定義される。 Preferably, the terms used herein are “Amultilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, HG W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH -4010 Basel, Switzerland).
以下の本明細書及び添付の特許請求の範囲を通して、文脈上他に必要な場合以外は、「を含む(comprise)」という単語、並びに「を含む(comprises)」及び「を含む(comprising)」等の変化形は、記載の整数若しくは工程又は整数若しくは工程の群を包含することを示唆するが、任意の他の整数若しくは工程又は整数若しくは工程の群を除外することを示唆しないと理解されよう。 Throughout the following specification and the appended claims, the word “comprise”, and “comprises” and “comprising”, unless otherwise required by context. Etc. will be understood to include the stated integer or step or integer or group of steps, but not to exclude any other integer or step or integer or group of steps. .
複数の文書が、本明細書の本文を通して引用される。上記のもの又は下記のもののいずれかに関わらず、本明細書で引用される文書(全ての特許、特許出願、科学的刊行物、製造業者の仕様書、取扱説明書等を含む)の各々は、その全体が参照により本明細書に援用される。本明細書のいかなる記載事項も、本発明が先の発明に基づくこのような開示に先行する権利を有しないことを承認するものとは解釈されない。 Multiple documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instruction manuals, etc.) The entirety of which is hereby incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
以下に、アルキル、ヘテロアルキル、ヘテロアリール、アルケニル及びアルキニルという用語の定義を提示する。これらの用語は、本明細書の残りにおけるその使用の各々の例において、それぞれ規定の意味及び好ましい意味を有する。ただし本明細書を通じたそれらの使用の幾つかの例では、これらの用語の好ましい意味が示される。 In the following, definitions of the terms alkyl, heteroalkyl, heteroaryl, alkenyl and alkynyl are presented. These terms have their respective defined and preferred meanings in each example of their use in the remainder of the specification. However, in some examples of their use throughout this specification, the preferred meaning of these terms is indicated.
「アルキル」という用語は、飽和の直鎖又は分岐鎖の炭素鎖を表す。好ましくは、該炭素鎖は、1個〜10個の炭素原子、すなわち1個、2個、3個、4個、5個、6個、7個、8個、9個又は10個の炭素原子を含む(例えばメチル、エチルメチル、エチル、プロピル、iso−プロピル、ブチル、iso−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチル、オクチル)。アルキル基は、特に記載がない限り(where indicated)、任意に置換される。 The term “alkyl” refers to a saturated straight or branched carbon chain. Preferably, the carbon chain has 1 to 10 carbon atoms, ie 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. (Eg, methyl, ethylmethyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl). Alkyl groups are optionally substituted unless otherwise indicated (where indicated).
「C1〜C4ヒドロキシアルキル」という用語は、モノ−又はポリ−ヒドロキシル化C1〜C4(すなわち1個、2個、3個又は4個の炭素原子を含む)アルキルを表す。好ましくは、この用語は、モノ−ヒドロキシル化C1〜C4アルキル基、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、ヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチルを表す。 The term “C 1 -C 4 hydroxyalkyl” refers to a mono- or poly-hydroxylated C 1 -C 4 (ie containing 1, 2, 3 or 4 carbon atoms) alkyl. Preferably, the term mono - represents hydroxylated C 1 -C 4 alkyl group, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyl -iso- propyl, 1-hydroxybutyl or 2-hydroxybutyl.
「ヘテロアルキル」という用語は、飽和の直鎖又は分岐鎖の炭素鎖を表す。好ましくは該炭素鎖は、1個〜9個の炭素原子、すなわち1個、2個、3個、4個、5個、6個、7個、8個、9個の炭素原子を含み(例えばメチル、エチル、プロピル、iso−プロピル、ブチル、iso−ブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチル、オクチル)、同じ又は異なるヘテロ原子が1回又は複数回、例えば1回、2回、3回割り込む(interrupted)。好ましくはヘテロ原子は、O、S及びNから選択される(例えばCH2−O−CH3、CH2−O−C2H5、C2H4−O−CH3、C2H4−O−C2H5等)。ヘテロアルキル基は、任意に置換される。 The term “heteroalkyl” refers to a saturated straight or branched carbon chain. Preferably the carbon chain comprises 1 to 9 carbon atoms, ie 1, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms (eg Methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl), the same or different heteroatoms one or more times, eg once, 2 Interrupted three times. Preferably the heteroatoms are selected from O, S and N (eg CH 2 —O—CH 3 , CH 2 —O—C 2 H 5 , C 2 H 4 —O—CH 3 , C 2 H 4 — O-C 2 H 5, etc.). Heteroalkyl groups are optionally substituted.
「ヘテロアリール」という用語は好ましくは、炭素原子の少なくとも1つが、1個、2個、3個若しくは4個(5員環に対して)、又は1個、2個、3個若しくは4個(6員環に対して)の同じ又は異なるヘテロ原子(好ましくはO、N及びSから選択される)により置き換えられた、5員又は6員の芳香族の単環式の環を表す。例は、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、1,2,5−オキサジアゾリル、1,2,3−オキサジアゾリル、ピロリル、イミダゾリル、ピラゾリル、1,2,3−トリアゾリル、チアゾリル、イソチアゾリル、1,2,3,−チアジアゾリル、1,2,5−チアジアゾリル、ピリジニル、ピリミジニル、ピラジニル、1,2,3−トリアジニル、1,2,4−トリアジニル及び1,3,5−トリアジニルである。 The term “heteroaryl” preferably has at least one carbon atom of 1, 2, 3 or 4 (relative to a 5-membered ring), or 1, 2, 3 or 4 (for a 5-membered ring). Represents a 5- or 6-membered aromatic monocyclic ring replaced by the same or different heteroatoms (preferably selected from O, N and S) of 6-membered rings. Examples are furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3 , -Thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl and 1,3,5-triazinyl.
本明細書で使用する場合の「単環式」は、任意の複数の融合した芳香族又はヘテロ芳香族の環を除く、芳香族又はヘテロ芳香族の環を1つだけ有する置換基を表す。 “Monocyclic” as used herein refers to a substituent having only one aromatic or heteroaromatic ring, excluding any plurality of fused aromatic or heteroaromatic rings.
「アルケニル」という用語は、1つ又は複数の二重結合を含有するオレフィン性の不飽和の炭素原子を表す。一例はプロペニルである。好ましくは、アルケニル鎖は、2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含む(例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル、オクテニル)。 The term “alkenyl” refers to an olefinically unsaturated carbon atom containing one or more double bonds. An example is propenyl. Preferably, the alkenyl chain contains 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms (eg ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl) .
「アルキニル」という用語は、1つ又は複数の三重結合を有する不飽和の炭素原子を表す。一例は、プロパルギルラジカルである。好ましくは、アルキニル鎖は、2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含む(例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル)。 The term “alkynyl” refers to an unsaturated carbon atom having one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain contains 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms (eg ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl).
本発明の化合物の好ましい一実施形態では、アルキルラジカル、アリールラジカル、アルケニルラジカル又はアルキニルラジカルにおける水素原子を、1つ又は(ore)複数のハロゲン原子により、互いに独立して置換してもよい。1つのラジカルは、トリフルオロメチルラジカルである。 In a preferred embodiment of the compounds of the invention, hydrogen atoms in an alkyl radical, aryl radical, alkenyl radical or alkynyl radical may be substituted independently of one another by one or more halogen atoms. One radical is a trifluoromethyl radical.
2つ以上のラジカルを互いに独立して選択することができる場合、「独立して」という用語は、該ラジカルが同じであってもよく又は異なっていてもよいことを意味する。 Where two or more radicals can be selected independently of each other, the term “independently” means that the radicals may be the same or different.
「薬学的に許容可能な塩」という用語は、本発明の化合物の塩を表す。本発明の化合物の好適な薬学的に許容可能な塩は、例えば、本発明の化合物の溶液を、薬学的に許容可能な酸、例えば塩酸、硫酸、フマル酸、マレイン酸、コハク酸、酢酸、安息香酸、クエン酸、酒石酸、炭酸又はリン酸の溶液と混合することにより形成することができる酸付加塩を含む。さらに、本発明の化合物が酸性部分を有する場合には、その好適な薬学的に許容可能な塩は、アルカリ金属塩(例えばナトリウム塩又はカリウム塩);アルカリ土類金属塩(例えばカルシウム塩又はマグネシウム塩);及び好適な有機リガンド(例えば、ハロゲン化物イオン、水酸化物イオン、カルボン酸イオン、硫酸イオン、リン酸イオン、硝酸イオン、アルキルスルホン酸イオン及びアリールスルホン酸イオン等の対アニオン(counteranions)を使用して形成されるアンモニウムカチオン、四級アンモニウムカチオン及びアミンカチオン)により形成される塩を含み得る。薬学的に許容可能な塩の例示的な例としては、酢酸塩、アジピン酸塩、アルギン酸塩、アスコルビン酸塩、アスパラギン酸塩、ベンゼンスルホン酸塩、安息香酸塩、重炭酸塩、重硫酸塩、重酒石酸塩、ホウ酸塩、臭化物塩、酪酸塩、エデト酸カルシウム、ショウノウ(camphorate)、カンファースルホン酸塩(camphorsulfonate)、カンシル酸塩、炭酸塩、塩化物塩、クエン酸塩、クラブラン酸塩、シクロペンタンプロピオン酸塩、ジグルコン酸塩、二塩酸塩、ドデシル硫酸塩、エデト酸塩、エジシル酸塩、エストール酸塩(estolate)、エシル酸塩、エタンスルホン酸塩、ギ酸塩、フマル酸塩、グルセプト酸塩、グルコヘプトン酸塩、グルコン酸塩、グルタミン酸塩、グリセロリン酸塩、グリコリルアルサニル酸塩(glycolylarsanilate)、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、ヘキシルレゾルシン酸塩(hexylresorcinate)、ヒドラバミン(hydrabamine)、臭化水素酸塩、塩酸塩、ヨウ化水素酸塩、2−ヒドロキシ−エタンスルホン酸塩、ヒドロキシナフトエ酸塩、ヨウ化物塩、イソチオネート(isothionate)、乳酸塩、ラクトビオン酸塩、ラウリン酸塩、ラウリル硫酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、マンデル酸塩、メシル酸塩、メタンスルホン酸塩、メチル硫酸塩、ムチン酸塩、2−ナフタレンスルホン酸塩、ナプシル酸塩、ニコチン酸塩、硝酸塩、N−メチルグルカミンアンモニウム塩、オレイン酸塩、シュウ酸塩、パモ酸塩(エンボン酸塩(embonate))、パルミチン酸塩、パントテン酸塩、ペクチン酸塩、過硫酸塩、3−フェニルプロピオン酸塩、リン酸塩/二リン酸塩、ピクリン酸塩、ピバル酸塩、ポリガラクツロン酸塩、プロピオン酸塩、サリチル酸塩、ステアリン酸塩、硫酸塩、塩基性酢酸塩、コハク酸塩、タンニン酸塩、酒石酸塩、テオクル酸塩、トシル酸塩、トリエチオジド(triethiodide)、ウンデカン酸塩、吉草酸塩等が挙げられるがこれらに限定されない(例えばBerge, S. M., et al, "Pharmaceutical Salts", Journal ofPharmaceutical Science, 1977, 66, 1-19を参照されたい)。或る特定の具体的な本発明の化合物は、化合物を塩基付加塩又は酸付加塩に変換することを可能とする塩基性及び酸性の両方の官能性(functionalities)を含有する。 The term “pharmaceutically acceptable salts” refers to salts of the compounds of the present invention. Suitable pharmaceutically acceptable salts of the compounds of the invention include, for example, solutions of the compounds of the invention with pharmaceutically acceptable acids such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, Includes acid addition salts that can be formed by mixing with a solution of benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium salts or magnesium). Salts); and suitable organic ligands (eg, counteranions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, alkylsulfonate ions and arylsulfonate ions) And ammonium salts formed using quaternary ammonium cations, quaternary ammonium cations and amine cations). Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, Bitartrate, borate, bromide, butyrate, calcium edetate, camhorate, camphorsulfonate, cansylate, carbonate, chloride salt, citrate, clavulanate , Cyclopentanepropionate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edicylate, estolate, esylate, ethanesulfonate, formate, fumarate, Gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, hep Tannate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, Iodide salt, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methyl Sulfate, mucinate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate) ), Palmitate, pantothenate, pectate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrin Acid salt, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, theocrate, tosylate, Examples include, but are not limited to, triethiodide, undecanoate, valerate, etc. (see, eg, Berge, SM, et al, “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19) ). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.
化合物の中性形態を、従来の方法で塩を塩基又は酸と接触させると共に親化合物を単離することにより、再生することができる。化合物の親形態は、或る特定の物理的特性(例えば極性溶媒における溶解性)において様々な塩形態と異なるが、それ以外は、塩形態は、本発明の目的に関して化合物の親形態と同等である。 The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (eg, solubility in polar solvents), but otherwise the salt form is equivalent to the parent form of the compound for purposes of the present invention. is there.
塩形態に加えて、本発明は、プロドラッグ形態の化合物を提供する。本明細書で記載される化合物のプロドラッグは、生理学的条件下で容易に化学的変化を受けて一般式(I)〜一般式(III)の化合物をもたらす化合物である。プロドラッグは、患者への該プロドラッグの投与後にin vivoの生理学的作用、例えば加水分解、代謝等により本発明の化合物へと化学的に修飾される薬理学的に活性な又は不活性な化合物である。加えて、ex vivo環境において化学的方法又は生化学的方法により、プロドラッグを本発明の化合物へと変換することができる。例えばプロドラッグを、好適な酵素を有する経皮パッチリザーバで与えた場合、本発明の化合物へとゆっくりと変換することができる。プロドラッグの製造及び使用に関与する適合性(suitability)及び技法は、当業者に既知である。エステルを含むプロドラッグの包括的な議論に関しては、Svensson and Tunek, Drug Metabolism Reviews 16.5 (1988)及びBundgaard, Design of Prodrugs,Elsevier (1985)を参照されたい。保護された(masked)酸性アニオンの例としては、様々なエステル、例えばアルキル(例えばメチル、エチル)、シクロアルキル(例えばシクロヘキシル)、アラルキル(例えばベンジル、p−メトキシベンジル)及びアルキルカルボニルオキシアルキル(例えばピバロイルオキシメチル)のエステルが挙げられる。アミンが、in vivoでエステラーゼにより切断されて遊離の薬剤及びホルムアルデヒドを放出する、アリールカルボニルオキシメチル置換誘導体として保護されている(Bungaard J. Med. Chem. 2503 (1989))。また、酸性のNH基を含有する薬剤、例えばイミダゾール、イミド、インドール等が、N−アシルオキシメチル基で保護されている(Bundgaard Design of Prodrugs, Elsevier (1985))。ヒドロキシ基が、エステル及びエーテルとして保護されている。欧州特許第0 039 051号(Sloan and Little, Apr. 11, 1981)は、マンニッヒ塩基のヒドロキサム酸プロドラッグ、それらの調製及び使用を開示している。 In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of general formula (I) to general formula (III). A prodrug is a pharmacologically active or inactive compound that is chemically modified to a compound of the present invention by in vivo physiological action such as hydrolysis, metabolism, etc. after administration of the prodrug to a patient It is. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when given in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in the production and use of prodrugs are known to those skilled in the art. For a comprehensive discussion of prodrugs containing esters, see Svensson and Tunek, Drug Metabolism Reviews 16.5 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985). Examples of masked acidic anions include various esters such as alkyl (eg methyl, ethyl), cycloalkyl (eg cyclohexyl), aralkyl (eg benzyl, p-methoxybenzyl) and alkylcarbonyloxyalkyl (eg And esters of pivaloyloxymethyl). Amines are protected as arylcarbonyloxymethyl substituted derivatives that are cleaved in vivo by esterases to release the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). In addition, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, are protected with an N-acyloxymethyl group (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups are protected as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich base hydroxamic acid prodrugs, their preparation and use.
本発明の化合物及びまた本発明によるその調製のための出発物質を、本明細書に示されるように、並びに代替的には当業者に既知の方法及び標準的手順により、すなわち文献(例えば標準的な作業においては、例えばHouben-Weyl, Methoden der organischen Chemie[Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart)中で説明されているように、当業者に既知であり、この反応に好適な反応条件下で、合成することができる。 The compounds of the invention and also the starting materials for their preparation according to the invention, as indicated herein and alternatively by methods and standard procedures known to the person skilled in the art, ie literature (eg standard For example, a suitable reaction for this reaction is known to those skilled in the art, for example as described in Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Can be synthesized under conditions.
必要に応じて出発物質を、反応混合物から該物質を単離せず、代わりに直ちに該物質をさらに本発明の化合物へと変換することにより、in situで形成することもできる。一方、反応を段階的に実施することが可能である。一般的な手順は、不特定の立体化学を有する化合物の調製に関するように示されていることに留意すべきである。しかしながら、このような手順は、特定の立体化学を有する(例えば、立体中心(sterogenic center)での立体化学が(S)又は(R)である)これらの化合物に概して適用可能である。加えて、多くの場合、既知の方法を使用して、例えば反転(inversion)により、1つの立体化学(例えば(R))を有する化合物を利用して反対の立体化学(すなわち(S))を有する化合物を製造することができる。 If necessary, the starting material can also be formed in situ by not isolating the material from the reaction mixture, but instead immediately converting the material further into the compounds of the invention. On the other hand, it is possible to carry out the reaction stepwise. It should be noted that the general procedure is shown as for the preparation of compounds with unspecified stereochemistry. However, such procedures are generally applicable to those compounds that have a particular stereochemistry (eg, the stereochemistry at the stereogenic center is (S) or (R)). In addition, the opposite stereochemistry (ie, (S)) is often utilized using known methods, eg, by inversion, using compounds having one stereochemistry (eg, (R)). Can be produced.
本発明の或る特定の化合物は、非溶媒和形態で、及び溶媒和形態(水和形態を含む)で存在し得る。概して、溶媒和形態は、非溶媒和形態と同等のものであり、本発明の範囲内に包含されることが意図される。本発明の或る特定の化合物は、複数の結晶形態又は非結晶形態で存在し得る。概して、全ての物理的形態が、本発明が意図する使用に関して同等であり、本発明の範囲内であることが意図される。 Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
或る特定の本発明の化合物は、不斉炭素原子(光学中心)又は二重結合を有する。ラセミ体、エナンチオマー、ジアステレオマー、幾何異性体、及び個々の異性体は全て、本発明の範囲内に包含されることが意図される。したがって、本発明の化合物は、立体異性体の混合物、特にエナンチオマーの混合物、及び精製された立体異性体、特に精製されたエナンチオマー、又は立体異性体として濃縮された混合物、特にエナンチオマーとして濃縮された混合物を含む。以下の式(I)〜式(III)により表される化合物の個々の異性体、及びその任意の全体的に又は部分的に平衡化した混合物も、本発明の範囲内に含まれる。本発明は、1つ又は複数のキラル中心が反転したその異性体との混合物としての、以下の式により表される化合物の個々の異性体も包含する。また、式(I)〜式(III)の化合物の全ての互変異性体及び互変異性体の混合物が、式(I)〜式(III)並びに好ましくはこれらに対応する式及び下位式(subformulas)の化合物の範囲内に含まれることが理解される。 Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds. The racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention. Accordingly, the compounds of the present invention are mixtures of stereoisomers, especially mixtures of enantiomers, and purified stereoisomers, particularly purified enantiomers, or mixtures enriched as stereoisomers, especially mixtures enriched as enantiomers. including. Also included within the scope of the invention are the individual isomers of the compounds represented by Formula (I) -Formula (III) below, and any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the following formulas as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, all tautomers and mixtures of tautomers of the compounds of formulas (I) to (III) are represented by formulas (I) to (III) and preferably the corresponding formulas and subformulas ( It is understood that they fall within the scope of compounds of subformulas).
得られたラセミ体を、それ自体既知の方法により機械的に又は化学的に、異性体に分割することができる。ジアステレオマーは好ましくは、光学活性分割剤との反応によりラセミ混合物から形成される。 The resulting racemate can be resolved into isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from racemic mixtures by reaction with optically active resolving agents.
好適な分割剤の例は、光学的に活性な酸、例えばD体及びL体の酒石酸、ジアセチル酒石酸、ジベンゾイル酒石酸、マンデル酸、リンゴ酸、乳酸、又は様々な光学的に活性なカンファースルホン酸、例えば−カンファースルホン酸である。光学活性分割剤(例えばジニトロベンゾイルフェニルグリシン)を充填したカラムを用いるエナンチオマー分割も有利であり、好適な溶離液の一例は、ヘキサン/イソプロパノール/アセトニトリル混合物である。 Examples of suitable resolving agents are optically active acids such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, For example -camphorsulfonic acid. Enantiomeric resolution using a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine) is also advantageous, and an example of a suitable eluent is a hexane / isopropanol / acetonitrile mixture.
標準的な精製プロセス、例えばクロマトグラフィ又は分別晶出等によりジアステレオマー分割を実施することもできる。 Diastereomeric resolution can also be carried out by standard purification processes, such as chromatography or fractional crystallization.
既に光学的に活性な出発物質を使用することによる上で記載される方法により、式(I)〜式(III)の光学的に活性な化合物を得ることも可能である。 It is also possible to obtain optically active compounds of the formulas (I) to (III) by the method described above by using already optically active starting materials.
本発明は、疾患又は障害の予防又は治療のための、新規な組成物、化合物、並びにこれらの化合物及び組成物の使用を提供する。 The present invention provides novel compositions, compounds, and uses of these compounds and compositions for the prevention or treatment of diseases or disorders.
第1の態様では、本発明は、式I: In a first aspect, the present invention provides compounds of formula I:
(式中、
R1は、単環式の5員又は6員のヘテロアリールであり;H;アルキル、好ましくは1個〜10個の炭素原子、すなわち1個、2個、3個、4個、5個、6個、7個、8個、9個又は10個の炭素原子を含むアルキル鎖、例えばメチル、エチル、プロピル、iso−プロピル、ブチル、iso−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチル又はオクチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−CN;ハロゲン、特にF、Cl、Br又はI;N−O(該窒素原子は該単環式の5員又は6員のヘテロアリールの一体部分である);−OH;アルコキシ、特にC1〜C6アルコキシ、例えばC1、C2、C3、C4、C5又はC6アルコキシ、好ましくはメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ、tert−ブトキシ、ペントキシ又はヘキソキシ;−SH;S−アルキル、特にC1〜C6 S−アルキル、例えばC1、C2、C3、C4、C5又はC6 S−アルキル;−NH2;NH−アルキル、特にC1〜C6 NH−アルキル、例えばC1、C2、C3、C4、C5又はC6 NH−アルキル;N−ビス−アルキル、好ましくはC1〜C6 N−ビス−アルキル、例えばC1、C2、C3、C4、C5又はC6 N−ビス−アルキル;NHOH;NMeOH;NMe(OMe);−NO2;−CF3;−OCF3、及びC1〜C4ヒドロキシアルキル、特にC1〜C4ヒドロキシアルキル、例えばC1、C2、C3又はC4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチルからなる群から選択される1つ又は複数の置換基で任意に置換され、
R2は、H、又はC1〜C4アルキル、すなわち1個〜4個の炭素原子、すなわち1個、2個、3個若しくは4個の炭素原子を含むアルキル基、例えばメチル、エチル、プロピル、iso−プロピル、ブチル若しくはiso−ブチルであり、
R3はH又は−CH3であり、
R4は、フェニル、又は単環式の5員若しくは6員のヘテロアリールであり;アルキル、好ましくは1個〜10個の炭素原子、すなわち1個、2個、3個、4個、5個、6個、7個、8個、9個又は10個の炭素原子を含むアルキル鎖、例えばメチル、エチル、プロピル、iso−プロピル、ブチル、iso−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチル又はオクチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;アルコキシ、特にC1〜C6アルコキシ、例えばC1、C2、C3、C4、C5又はC6アルコキシ、好ましくはメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ、tert−ブトキシ、ペントキシ又はヘキソキシ;ハロゲン、特にF、Cl、Br又はI;−CN;−CF3;−OCF3;C1〜C4ヒドロキシアルキル、特にC1〜C4ヒドロキシアルキル、例えばC1、C2、C3又はC4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;−OH;−SH;S−アルキル、特にC1〜C6 S−アルキル、例えばC1、C2、C3、C4、C5又はC6 S−アルキル;−CN;N−ビス−アルキル、好ましくはC1〜C6 N−ビス−アルキル、例えばC1、C2、C3、C4、C5又はC6 N−ビス−アルキル;シアノアセチレン;−NO2;−NR7R8、好ましくは−NH2又はNH−アルキル、より好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3アルキル又は−NH−C4アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;N−O(該窒素原子は該単環式の5員又は6員のヘテロアリールの一体部分である)、並びに(R4がフェニルである場合)ジオキシメチレン架橋(−O−CH2−O−)を共に形成する2つの置換基からなる群から選択される1つ又は複数の置換基で任意に置換され、
R5はH又は−CH3であり、
R6は、C1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル又はiso−ブチルであり、
R7は、H、又はアルキル、好ましくは1個〜10個の炭素原子、すなわち1個、2個、3個、4個、5個、6個、7個、8個、9個若しくは10個の炭素原子を含むアルキル鎖、例えばメチル、エチル、プロピル、iso−プロピル、ブチル、iso−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチル若しくはオクチルであり、
R8は、H、又はC1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル若しくはiso−ブチルであり、
ただしR1は5−クロロ−チオフェン−2−イルではなく、R5及びR3は同時にHではない)
による構造を有する化合物に関する。
(Where
R 1 is monocyclic 5 or 6 membered heteroaryl; H; alkyl, preferably 1 to 10 carbon atoms, ie 1, 2, 3, 4, 5, Alkyl chains containing 6, 7, 8, 9 or 10 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl Alkenyl, especially alkenyl chains containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms, eg ethenyl, 1-propenyl, 2; -Propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hex Alkynyl, preferably alkynyl containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -CN; halogen, especially F, Cl, Br or I; N—O (the nitrogen atom is an integral part of the monocyclic 5- or 6-membered heteroaryl); —OH; alkoxy, especially C 1 -C 6 alkoxy, such as C 1 , C 2, C 3, C 4, C 5 or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, iso- propoxy, butoxy, iso- butoxy, tert- butoxy, pentoxy or hexoxy; -SH; S- alkyl, especially C 1 -C 6 S- alkyl, e.g. C 1, C 2, C 3 , C 4, C 5 or C 6 S- alkyl; -NH 2 ; NH- alkyl, especially C 1 -C 6 NH- alkyl, e.g. C 1, C 2, C 3 , C 4, C 5 or C 6 NH- alkyl; N- bis - alkyl, preferably C 1 -C 6 N- bis - alkyl, such as C 1, C 2, C 3 , C 4, C 5 or C 6 N- bis - alkyl; NHOH; NMeOH; NMe (OMe ); - NO 2; -CF 3; -OCF 3 , and C 1 -C 4 hydroxyalkyl, especially C 1 -C 4 hydroxyalkyl, e.g. C 1, C 2, C 3 or C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, human Rokishipuropiru or hydroxyl -iso- propyl, are optionally substituted with one or more substituents selected from the group consisting of 1-hydroxybutyl or 2-hydroxybutyl,
R 2 is H or C 1 -C 4 alkyl, ie 1 to 4 carbon atoms, ie an alkyl group containing 1, 2, 3 or 4 carbon atoms, for example methyl, ethyl, propyl , Iso-propyl, butyl or iso-butyl,
R 3 is H or —CH 3 ;
R 4 is phenyl or monocyclic 5 or 6 membered heteroaryl; alkyl, preferably 1 to 10 carbon atoms, ie 1, 2, 3, 4, 5 An alkyl chain containing 6, 7, 8, 9 or 10 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl or Octyl; alkenyl, especially alkenyl chains containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pen Alkynyl, preferably alkynyl, containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, ethynyl, hexenyl, heptenyl or octenyl Ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; alkoxy, especially C 1- C 6 alkoxy, such as C 1 , C 2 , C 3 , C 4 , C 5 or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy or hexoxy; halogen, in particular F, Cl, Br or I; -CN; -CF 3; -OCF 3; 1 -C 4 hydroxyalkyl, especially C 1 -C 4 hydroxyalkyl, e.g. C 1, C 2, C 3 or C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxy -iso- propyl, 1-hydroxy butyl or 2-hydroxybutyl; -OH; -SH; S- alkyl, especially C 1 -C 6 S- alkyl, e.g. C 1, C 2, C 3 , C 4, C 5 or C 6 S- alkyl; - CN; N-bis - alkyl, preferably C 1 -C 6 N-bis - alkyl, such as C 1, C 2, C 3 , C 4, C 5 or C 6 N-bis - alkyl; cyano acetylene; -NO 2; -NR 7 R 8, preferably -NH 2 or NH- alkyl, more preferably -NH 2 or -NH-C 1 ~C 4 alkyl That -NH-CH 3, -NH- ethyl, -NH-C 3 alkyl or -NH-C 4 alkyl, and most preferably -NH 2, NH (CH 3) or N (CH 3) 2; -C ( O) R 6 , preferably acetyl, propionyl, iso-propionyl, butyryl or iso-butyryl; N—O, where the nitrogen atom is an integral part of the monocyclic 5 or 6 membered heteroaryl, and Optionally substituted with one or more substituents selected from the group consisting of two substituents that together form a dioxymethylene bridge (—O—CH 2 —O—) (when R 4 is phenyl). ,
R 5 is H or —CH 3 ;
R 6 is C 1 -C 4 alkyl, in particular methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl,
R 7 is H or alkyl, preferably 1 to 10 carbon atoms, ie 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 An alkyl chain containing 5 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl;
R 8 is H or C 1 -C 4 alkyl, especially methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl,
Where R 1 is not 5-chloro-thiophen-2-yl and R 5 and R 3 are not H at the same time)
To a compound having the structure
好ましい一実施形態では、R4は3−アルコキシ置換ピリダジン−6−イルではなく、R3及びR5は同時にHではない。 In one preferred embodiment, R 4 is not 3-alkoxy substituted pyridazin-6-yl and R 3 and R 5 are not H at the same time.
R1が、メチル、エチル、メトキシ、−OC2H5、−CF3、−OCF3、CN、F及び−NH2からなる群から選択される置換基で任意に置換された、単環式の5員又は6員のヘテロアリールである化合物も好ましい。 Monocyclic, wherein R 1 is optionally substituted with a substituent selected from the group consisting of methyl, ethyl, methoxy, —OC 2 H 5 , —CF 3 , —OCF 3 , CN, F, and —NH 2 Also preferred are compounds of 5 or 6 membered heteroaryl.
化合物のさらなる好ましい一実施形態では、R2及びR5はHであり、R1は、メチル、エチル、メトキシ、−OC2H5、−CF3、−OCF3、CN、F及び−NH2からなる群から選択される置換基で任意に置換された、単環式の5員又は6員のヘテロアリールである。 In a further preferred embodiment of the compound, R 2 and R 5 are H and R 1 is methyl, ethyl, methoxy, —OC 2 H 5 , —CF 3 , —OCF 3 , CN, F and —NH 2. Monocyclic 5- or 6-membered heteroaryl, optionally substituted with a substituent selected from the group consisting of:
本発明の化合物のR4置換基及び/又はR1置換基は、好ましい実施形態では、ヘテロ原子を1つだけ有する場合があり、及び/又は2つ未満若しくは3つ未満の置換基で置換される場合がある。 The R 4 substituent and / or R 1 substituent of the compounds of the present invention may, in preferred embodiments, have only one heteroatom and / or be substituted with less than 2 or less than 3 substituents. There is a case.
本発明の化合物のさらなる好ましい一実施形態は、以下の置換基を有する:R2及びR5がHであり、R1が、メチル、エチル、メトキシ、−OC2H5、−CF3、−OCF3、CN、F及び−NH2からなる群から選択される置換基で任意に置換された、単環式の5員若しくは6員のヘテロアリールであり、R4基が2つ未満若しくは3つ未満の置換基で置換され、並びに/又はR4が単環式の5員若しくは6員のヘテロアリールである場合、R4がヘテロ原子を1つだけ含むことがこの文脈では好ましい。 A further preferred embodiment of the compounds of the invention has the following substituents: R 2 and R 5 are H and R 1 is methyl, ethyl, methoxy, —OC 2 H 5 , —CF 3 , — A monocyclic 5- or 6-membered heteroaryl optionally substituted with a substituent selected from the group consisting of OCF 3 , CN, F and —NH 2 , wherein R 4 groups are less than 2 or 3 It is preferred in this context that R 4 contains only one heteroatom when it is substituted with less than two substituents and / or when R 4 is a monocyclic 5 or 6 membered heteroaryl.
好ましい一実施形態では、本発明の化合物は、式II: In one preferred embodiment, the compounds of the invention have formula II:
による構造を有する。 It has the structure by.
式III: Formula III:
による構造を有する本発明の化合物も好ましい。 Also preferred are compounds of the invention having the structure according to
本発明の化合物の好ましい一実施形態では、R4は、式IV: In one preferred embodiment of the compounds of the present invention, R 4 is of the formula IV:
(式中、
R9及びR10は各々個々に、H;C1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル若しくはiso−ブチル;C1〜C4アルケニル、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル若しくはsec−ブテニル;C1〜C4アルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル若しくは3−ブチニル;−CN;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル若しくはiso−ブチリル;シアノアセチレン;ハロゲン、特にF、Cl、Br若しくはI;−OH;C1〜C4アルコキシ、例えばメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ若しくはtert−ブトキシ;−SH;C1〜C4 S−アルキル、例えばC1、C2、C3若しくはC4 S−アルキル;−NH2;C1〜C4 NH−アルキル、例えばC1、C2、C3若しくはC4 NH−アルキル;C1〜C4 N−ビス−アルキル、例えばC1、C2、C3若しくはC4 N−ビス−アルキル;−NO2;−CF3;−OCF3;及びC1〜C4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル若しくはヒドロキシル−iso−プロピル、1−ヒドロキシブチル若しくは2−ヒドロキシブチルからなる群から選択され;又はR9及びR10は、ジオキシメチレン架橋(−O−CH2−O−)を共に形成し、
R11及びR12は各々個々に、H;C1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル又はiso−ブチル;C1〜C4アルケニル、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル又はsec−ブテニル;C1〜C4アルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル又は3−ブチニル;−CN;ハロゲン、特にF、Cl、Br又はI;−OH;C1〜C4アルコキシ、例えばメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ又はtert−ブトキシ;−SH;C1〜C4 S−アルキル、例えばC1、C2、C3又はC4 S−アルキル;−CF3;−OCF3;−NH2;−N(CH3)2、及びC1〜C4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチルからなる群から選択され、
R6は上で示した意味を有し(例えばメチル、エチル、プロピル、iso−プロピル、ブチル又はiso−ブチルであり)、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
による構造を有する。
(Where
R 9 and R 10 are each independently H; C 1 -C 4 alkyl, especially methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl; C 1 -C 4 alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl or sec- butenyl; C 1 -C 4 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl; -CN; -C (O) R 6, preferably acetyl, propionyl, iso- propionyl, butyryl or iso- butyryl; cyano acetylene; halogen, especially F, Cl, Br or I; - OH; C 1 ~C 4 alkoxy, such as methoxy, ethoxy, propoxy Alkoxy, iso- propoxy, butoxy, iso- butoxy or tert- butoxy; -SH; C 1 ~C 4 S- alkyl, e.g. C 1, C 2, C 3 or C 4 S- alkyl; -NH 2; C 1 -C 4 NH- alkyl, e.g. C 1, C 2, C 3 or C 4 NH- alkyl; C 1 ~C 4 N- bis - alkyl, such as C 1, C 2, C 3 or C 4 N-bis - alkyl; -NO 2; -CF 3; -OCF 3; and C 1 -C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxy -iso- propyl, consisting of 1-hydroxybutyl or 2-hydroxybutyl It is selected from the group; or R 9 and R 10, dioxymethylene crosslinking the (-O-CH 2 -O-) Formed in,
R 11 and R 12 are each independently H; C 1 -C 4 alkyl, in particular methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl; C 1 -C 4 alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl or sec- butenyl; C 1 -C 4 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl; -CN; halogen, especially F, Cl, Br or I; -OH; C 1 ~C 4 alkoxy, such as methoxy, ethoxy, propoxy, iso- propoxy, butoxy, iso- butoxy or tert - butoxy; -SH; C 1 ~C 4 S- alkyl, e.g. C 1, C 2, C 3 also C 4 S- alkyl; -CF 3; -OCF 3; -NH 2; -N (CH 3) 2, and C 1 -C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxy -iso- propyl , Selected from the group consisting of 1-hydroxybutyl or 2-hydroxybutyl,
R 6 has the meaning indicated above (for example methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl)
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
It has the structure by.
R4が式(IV)の構造を有する好ましい実施形態では、(a)R9がCNであり、R10、R11及びR12がHである;(b)R10がCNであり、R9、R11及びR12がHである;(c)R9、R10及びR11がHであり、R12がCNである;(d)R9がエチニルであり、R10、R11及びR12がHである;(e)R10がエチニルであり、R9、R11及びR12がHである;(f)R9、R10及びR11がHであり、R12がエチニルである;(g)R9がCNであり、R10、R11及びR12のうちの1つが、OH、若しくはC1〜C4アルコキシ、例えばメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ若しくはtert−ブトキシである;(h)R10がCNであり、R9、R11及びR12のうちの1つ、好ましくはR9が、ハロゲン、特にF、OH、若しくはC1〜C4アルコキシ、例えばメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ若しくはtert−ブトキシである;又は(i)R9、R10及びR11のうちの1つ、好ましくはR9が、OH、若しくはC1〜C4アルコキシ、例えばメトキシ、エトキシ、プロポキシ、iso−プロポキシ、ブトキシ、iso−ブトキシ若しくはtert−ブトキシであり、R12がCNである;好ましくはR10がCNであり、R9がOH、若しくはC1〜C4アルコキシ、好ましくはメトキシであることが特に好ましい。 In a preferred embodiment where R 4 has the structure of formula (IV): (a) R 9 is CN and R 10 , R 11 and R 12 are H; (b) R 10 is CN; 9 , R 11 and R 12 are H; (c) R 9 , R 10 and R 11 are H and R 12 is CN; (d) R 9 is ethynyl and R 10 , R 11 And R 12 is H; (e) R 10 is ethynyl, R 9 , R 11 and R 12 are H; (f) R 9 , R 10 and R 11 are H, and R 12 is (G) R 9 is CN and one of R 10 , R 11 and R 12 is OH, or C 1 -C 4 alkoxy, such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy , Iso-butoxy or tert-butoxy (H) R 10 is CN, one of R 9, R 11 and R 12, preferably R 9 is halogen, in particular F, OH, or C 1 -C 4 alkoxy, such as methoxy, ethoxy, Propoxy, iso-propoxy, butoxy, iso-butoxy or tert-butoxy; or (i) one of R 9 , R 10 and R 11 , preferably R 9 is OH, or C 1 -C 4. Alkoxy, eg methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy or tert-butoxy, R 12 is CN; preferably R 10 is CN and R 9 is OH, or C 1- C 4 alkoxy, particularly preferably preferably methoxy.
好ましくは上記の化合物において、R9及びR12が同時にメトキシである場合はない。 Preferably in the above compounds, R 9 and R 12 are not simultaneously methoxy.
R11及びR12がHである本発明の化合物は、さらに好ましい。 More preferred are compounds of the invention wherein R 11 and R 12 are H.
本発明の化合物の別の好ましい実施形態では、R3はメチルであり、R2はH、メチル又はエチル、好ましくはHであり、R5はHである。 In another preferred embodiment of the compounds of the present invention, R 3 is methyl, R 2 is H, methyl or ethyl, preferably H, and R 5 is H.
本発明の化合物の好ましい一実施形態では、R4は、式V: In a preferred embodiment of the compounds of the present invention, R 4 is of the formula V:
(式中、
A、B、D及びEは各々個々に、窒素原子、CR13及びN−Oからなる群から選択され、
Gは、酸素原子、硫黄原子及びNR14からなる群から選択され、
R13は、H;C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−OH;−SH;S−アルキル、例えばC1、C2又はC3 S−アルキル;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3アルキル又は−NH−C4アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;−NO2;−CN;−C(O)R6;アセチレン;シアノアセチレン;C1〜C4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル、並びにR4を式(I)〜式(III)のいずれかによる化合物と連結するσ(シグマ)結合からなる群から選択され、
R14は、H、C1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル又はiso−ブチル、及びより好ましくはメチル、エチル、プロピル又はiso−プロピル;並びにR4を式(I)〜式(III)のいずれかによる化合物と連結するσ(シグマ)結合からなる群から選択され、
R15及びR16は各々個々に、H、又はC1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル若しくはiso−ブチルであり、
R6は上で示した意味を有し(例えばメチル、エチル、プロピル、iso−プロピル、ブチル又はiso−ブチルであり)、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
による構造を有する。
(Where
A, B, D and E are each individually selected from the group consisting of a nitrogen atom, CR 13 and N—O;
G is selected from the group consisting of an oxygen atom, a sulfur atom and NR 14 ;
R 13 is H; C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or iso-propoxy; -OH; -SH; S- alkyl, for example C 1, C 2 or C 3 S- alkyl; -CF 3; -OCF 3; halogen, especially F, Cl, Br or I; -NR 15 R 16, preferably -NH 2 or -NH-C 1 -C 4 alkyl, i.e. -NH-CH 3, -NH- ethyl, -NH-C 3 alkyl or -NH-C 4 alkyl, and most preferably -NH 2, NH (CH 3) or N (CH 3 ) 2 ; —NO 2 ; —CN; —C (O) R 6 ; acetylene; cyanoacetylene; C 1 -C 4 hydroxyalkyl, such as hydroxymethyl, hydroxye The group consisting of til, hydroxypropyl or hydroxyl-iso-propyl, 1-hydroxybutyl or 2-hydroxybutyl, and σ (sigma) bond linking R 4 with a compound according to any of formulas (I) to (III) Selected from
R 14 is, H, C 1 -C 4 alkyl, in particular methyl, ethyl, propyl, iso- propyl, butyl or iso- butyl, and more preferably methyl, ethyl, propyl or iso- propyl, and the R 4 formula ( Selected from the group consisting of σ (sigma) bonds linked to compounds according to any of I) to formula (III),
R 15 and R 16 are each independently H or C 1 -C 4 alkyl, in particular methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl,
R 6 has the meaning indicated above (for example methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl)
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
It has the structure by.
本発明の化合物の別の好ましい実施形態では、R4は、式VI: In another preferred embodiment of the compounds of the invention, R 4 is of the formula VI:
(式中、
L及びTは各々個々に、CH基又は窒素原子又はN−Oであり、
M、N及びQは各々個々に、窒素原子、CR17基及びN−Oからなる群から選択され、
R17は、H;C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3アルキル又は−NH−C4アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;アセチレン;シアノアセチレン、並びに−CNからなる群から選択され、
R15及びR16は各々個々に、H、又はC1〜C4アルキル、特にメチル、エチル、プロピル、iso−プロピル、ブチル若しくはiso−ブチルであり、
R6は上で示した意味を有し(例えばメチル、エチル、プロピル、iso−プロピル、ブチル又はiso−ブチルであり)、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
による構造を有する。
(Where
L and T are each independently a CH group, a nitrogen atom or N—O,
M, N and Q are each independently selected from the group consisting of a nitrogen atom, a CR 17 group and N—O;
R 17 is H; C 1 -C 3 alkyl, particularly methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or iso-propoxy; —CF 3 ; —OCF 3 ; Halogen, especially F, Cl, Br or I; —OH; —NO 2 ; —SH; C 1 -C 3 S-alkyl, for example C 1 , C 2 or C 3 S-alkyl; —NR 15 R 16 , preferably Is —NH 2 or —NH—C 1 -C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 alkyl or —NH—C 4 alkyl, and most preferably —NH 2 , NH (CH 3) or N (CH 3) 2; C 1 ~C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxy - so- propyl, 1-hydroxybutyl or 2-hydroxybutyl; -C (O) R 6, preferably acetyl, propionyl, iso- propionyl, butyryl or iso- butyryl; acetylene; cyano acetylene, as well as from the group consisting of -CN Selected
R 15 and R 16 are each independently H or C 1 -C 4 alkyl, in particular methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl,
R 6 has the meaning indicated above (for example methyl, ethyl, propyl, iso-propyl, butyl or iso-butyl)
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
It has the structure by.
R4が、 R 4 is
(式中、
R18及びR19は各々個々に、H;C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3−アルキル又は−NH−C4−アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4−ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;シアノアセチレン、並びに−CNからなる群から選択され、
R15及びR16は、上で示した意味及び好ましい意味を有する)
からなる群から選択される、本発明の化合物も好ましい。
(Where
R 18 and R 19 are each independently H; C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or iso-propoxy; 3; -OCF 3; halogen, especially F, Cl, Br or I; -OH; -NO 2; -SH ; C 1 ~C 3 S- alkyl, for example C 1, C 2 or C 3 S- alkyl; - NR 15 R 16 , preferably —NH 2 or —NH—C 1 -C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 -alkyl or —NH—C 4 -alkyl, and most preferably -NH 2, NH (CH 3) or N (CH 3) 2; C 1 ~C 4 - hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxy Cypropyl or hydroxyl-iso-propyl, 1-hydroxybutyl or 2-hydroxybutyl; alkenyl, especially 2-8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 Alkenyl chains containing 1 carbon atom such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2- Pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl or octenyl; alkynyl, preferably 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 Alkynyl containing a number of carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butyn , 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -C (O) R 6, preferably acetyl, propionyl, iso- propionyl, butyryl or iso- butyryl; cyano acetylene, And -CN,
R 15 and R 16 have the meanings and preferred meanings given above)
Also preferred are compounds of the invention selected from the group consisting of
好ましい一実施形態では、R18はHであり、上で示した構造におけるR19は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3−アルキル又は−NH−C4−アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4−ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;シアノアセチレン、並びに−CNからなる群から選択される。この文脈でのR19の最も好ましい意味は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、特にメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3、−CN、−NO2、又はハロゲン、特にF、Cl、Br若しくはIであり、メチル、メトキシ、CF3又は−CNが最も好ましい意味である。 In one preferred embodiment, R 18 is H and R 19 in the structure shown above is C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, eg methoxy , ethoxy, propoxy or iso- propoxy; -CF 3; -OCF 3; halogen, especially F, Cl, Br or I; -OH; -NO 2; -SH ; C 1 ~C 3 S- alkyl, such as C 1 , C 2 or C 3 S-alkyl; —NR 15 R 16 , preferably —NH 2 or —NH—C 1 to C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 — Alkyl or —NH—C 4 -alkyl, and most preferably —NH 2 , NH (CH 3 ) or N (CH 3 ) 2 ; C 1 -C 4 -hydroxyalkyl, such as hydride Roxymethyl, hydroxyethyl, hydroxypropyl or hydroxyl-iso-propyl, 1-hydroxybutyl or 2-hydroxybutyl; alkenyl, in particular 2-8 carbon atoms, ie 2, 3, 4, 5, 6 Alkenyl chains containing 1, 7 or 8 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl or octenyl; alkynyl, preferably 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6 Alkynyl containing 7 or 8 carbon atoms, eg ethynyl, 1-propynyl, 2-propynyl 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -C (O) R 6, preferably acetyl, propionyl, iso- Selected from the group consisting of propionyl, butyryl or iso-butyryl; cyanoacetylene, and -CN. The most preferred meaning of R 19 in this context is C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, especially methoxy, ethoxy, propoxy or iso-propoxy; 3 ; —OCF 3 , —CN, —NO 2 , or halogen, especially F, Cl, Br or I, with methyl, methoxy, CF 3 or —CN being the most preferred meaning.
別の好ましい実施形態では、R19はHであり、上で示した構造におけるR18は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3−アルキル又は−NH−C4−アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4−ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;シアノアセチレン、並びに−CNからなる群から選択される。この文脈でのR18の最も好ましい意味は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、特にメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3、−CN、−NO2、又はハロゲン、特にF、Cl、Br若しくはIであり、メチル、メトキシ、CF3又は−CNが最も好ましい意味である。 In another preferred embodiment, R 19 is H, and R 18 in the structure shown above is C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or iso- propoxy; -CF 3; -OCF 3; halogen, especially F, Cl, Br or I; -OH; -NO 2; -SH ; C 1 ~C 3 S- alkyl, for example C 1 , C 2 or C 3 S-alkyl; —NR 15 R 16 , preferably —NH 2 or —NH—C 1 -C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 - alkyl or -NH-C 4 - alkyl, and most preferably -NH 2, NH (CH 3) or N (CH 3) 2; C 1 ~C 4 - hydroxyalkyl, for example human Droxymethyl, hydroxyethyl, hydroxypropyl or hydroxyl-iso-propyl, 1-hydroxybutyl or 2-hydroxybutyl; alkenyl, in particular 2-8 carbon atoms, ie 2, 3, 4, 5, 6 Alkenyl chains containing 1, 7 or 8 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl or octenyl; alkynyl, preferably 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6 Alkynyl containing 7 or 8 carbon atoms, for example ethynyl, 1-propynyl, 2-propini , 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -C (O) R 6, preferably acetyl, propionyl, iso -Propionyl, butyryl or iso-butyryl; selected from the group consisting of cyanoacetylene, and -CN. The most preferred meaning of R 18 in this context is C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, especially methoxy, ethoxy, propoxy or iso-propoxy; 3 ; —OCF 3 , —CN, —NO 2 , or halogen, especially F, Cl, Br or I, with methyl, methoxy, CF 3 or —CN being the most preferred meaning.
別の好ましい実施形態では、R18及びR19は各々個々に、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3−アルキル又は−NH−C4−アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4−ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;シアノアセチレン、並びに−CNからなる群から選択される。この文脈でのR18及びR19の最も好ましい意味は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、特にメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3、−CN、−NO2、又はハロゲン、特にF、Cl、Br若しくはIであり、メチル、メトキシ、CF3又は−CNが最も好ましい意味である。 In another preferred embodiment, R 18 and R 19 are each independently C 1 -C 3 alkyl, in particular methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, eg methoxy, ethoxy, propoxy or iso - propoxy; -CF 3; -OCF 3; halogen, especially F, Cl, Br or I; -OH; -NO 2; -SH ; C 1 ~C 3 S- alkyl, for example C 1, C 2 or C 3 S-alkyl; —NR 15 R 16 , preferably —NH 2 or —NH—C 1 -C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 -alkyl or —NH—C 4 - alkyl, and most preferably -NH 2, NH (CH 3) or N (CH 3) 2; C 1 ~C 4 - hydroxyalkyl, such as hydroxymethyl, hydrin Roxyethyl, hydroxypropyl or hydroxyl-iso-propyl, 1-hydroxybutyl or 2-hydroxybutyl; alkenyl, in particular 2-8 carbon atoms, ie 2, 3, 4, 5, 6, 7 Alkenyl chains containing 1 or 8 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl or octenyl; alkynyl, preferably 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 Or alkynyl containing 8 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2 Butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -C (O) R 6, preferably acetyl, propionyl, iso- propionyl, butyryl or iso- Butyryl; selected from the group consisting of cyanoacetylene and -CN. Most preferred meanings of R 18 and R 19 in this context are C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, especially methoxy, ethoxy, propoxy or iso-propoxy. ; -CF 3; -OCF 3, -CN , -NO 2, or halogen, in particular F, Cl, Br or I, methyl, methoxy, CF 3 or -CN are the most preferred meanings.
本発明の化合物の別の好ましい実施形態では、R2はHであり、R4は、 In another preferred embodiment of the compounds of the present invention, R 2 is H and R 4 is
(式中、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
からなる群から選択される。
(Where
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
Selected from the group consisting of
本発明の化合物のさらなる好ましい一実施形態では、R1は、好ましくは以下に示されるように任意に置換された、5員のヘテロ芳香族残基であり;好ましくは、好ましくは以下に示されるように任意に置換された、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、1,2,5−オキサジアゾリル、1,2,3−オキサジアゾリル、ピロリル、イミダゾリル、ピラゾリル、1,2,3−トリアゾリル、チアゾリル、イソチアゾリル、1,2,3,−チアジアゾリル及び1,2,5−チアジアゾリルからなる群から選択され;より好ましくは、 In a further preferred embodiment of the compounds of the invention, R 1 is preferably a 5-membered heteroaromatic residue, optionally substituted as shown below; preferably, as shown below Optionally substituted furanyl, thiophenyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, Selected from the group consisting of 1,2,3-thiadiazolyl and 1,2,5-thiadiazolyl; more preferably,
からなる群から選択される(ここで、
R1は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3アルキル又は−NH−C4アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;シアノアセチレン、並びに−CNからなる群から選択される1つ又は複数の、好ましくは1つの置換基で任意にさらに置換され、
*は、R1と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)。
Selected from the group consisting of (where
R 1 is C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or iso-propoxy; —CF 3 ; —OCF 3 ; halogen, in particular F, Cl, Br or I; -OH; -NO 2; -SH ; C 1 ~C 3 S- alkyl, for example C 1, C 2 or C 3 S- alkyl; -NR 15 R 16, preferably - NH 2 or —NH—C 1 -C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 alkyl or —NH—C 4 alkyl, and most preferably —NH 2 , NH (CH 3) or N (CH 3) 2; C 1 ~C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxy -iso Propyl, 1-hydroxybutyl or 2-hydroxybutyl; alkenyl, especially containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms Alkenyl chains such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl or octenyl; alkynyl, preferably alkynyl containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms For example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -C (O) R 6, preferably acetyl, propionyl, iso- propionyl, butyryl or iso- butyryl; is cyano acetylene, as well as from the group consisting of -CN Optionally further substituted with one or more, preferably one substituent,
* Indicates a bond between R 1 and a compound according to any of formulas (I) to (III)).
上で概説したR1の好ましい実施形態において、R2がHであることが特に好ましい。 In the preferred embodiment of R 1 outlined above, it is particularly preferred that R 2 is H.
R1が、好ましくは以下に示されるように任意に置換された、単環式の(monocylic)6員のヘテロ芳香族残基であり;好ましくは、好ましくは以下に示されるように任意に置換された、ピリジニル、ピリミジニル、ピラジニル、1,2,3−トリアジニル、1,2,4−トリアジニル及び1,3,5−トリアジニルからなる群から選択され;又はより好ましくは、 R 1 is a monocylic 6-membered heteroaromatic residue, preferably optionally substituted as shown below; preferably, optionally substituted as shown below Or selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl and 1,3,5-triazinyl;
からなる群から選択される、本発明による化合物も好ましい(ここで、
R1は、C1〜C3アルキル、特にメチル、エチル、プロピル又はiso−プロピル;C1〜C3アルコキシ、例えばメトキシ、エトキシ、プロポキシ又はiso−プロポキシ;−CF3;−OCF3;ハロゲン、特にF、Cl、Br又はI;−OH;−NO2;−SH;C1〜C3 S−アルキル、例えばC1、C2又はC3 S−アルキル;−NR15R16、好ましくは−NH2又は−NH−C1〜C4アルキル、すなわち−NH−CH3、−NH−エチル、−NH−C3アルキル又は−NH−C4アルキル、及び最も好ましくは−NH2、NH(CH3)又はN(CH3)2;C1〜C4ヒドロキシアルキル、例えばヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル又はヒドロキシル−iso−プロピル、1−ヒドロキシブチル又は2−ヒドロキシブチル;アルケニル、特に2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルケニル鎖、例えばエテニル、1−プロペニル、2−プロペニル、iso−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、iso−ブテニル、sec−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、ヘキセニル、ヘプテニル又はオクテニル;アルキニル、好ましくは2個〜8個の炭素原子、すなわち2個、3個、4個、5個、6個、7個又は8個の炭素原子を含むアルキニル、例えばエチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、ヘキシニル、ペンチニル又はオクチニル;−C(O)R6、好ましくはアセチル、プロピオニル、iso−プロピオニル、ブチリル又はiso−ブチリル;シアノアセチレン、並びに−CNからなる群から選択される1つ又は複数の、好ましくは1つの置換基で任意にさらに置換され、
*は、R1と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)。
Also preferred are compounds according to the invention selected from the group consisting of:
R 1 is C 1 -C 3 alkyl, especially methyl, ethyl, propyl or iso-propyl; C 1 -C 3 alkoxy, such as methoxy, ethoxy, propoxy or iso-propoxy; —CF 3 ; —OCF 3 ; halogen, in particular F, Cl, Br or I; -OH; -NO 2; -SH ; C 1 ~C 3 S- alkyl, for example C 1, C 2 or C 3 S- alkyl; -NR 15 R 16, preferably - NH 2 or —NH—C 1 -C 4 alkyl, ie —NH—CH 3 , —NH-ethyl, —NH—C 3 alkyl or —NH—C 4 alkyl, and most preferably —NH 2 , NH (CH 3) or N (CH 3) 2; C 1 ~C 4 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxy -iso Propyl, 1-hydroxybutyl or 2-hydroxybutyl; alkenyl, especially containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms Alkenyl chains such as ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso-butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl or octenyl; alkynyl, preferably alkynyl containing 2 to 8 carbon atoms, ie 2, 3, 4, 5, 6, 7 or 8 carbon atoms For example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl 3-pentynyl, 4-pentynyl, hexynyl, pentynyl or octynyl; -C (O) R 6, preferably acetyl, propionyl, iso- propionyl, butyryl or iso- butyryl; is cyano acetylene, as well as from the group consisting of -CN Optionally further substituted with one or more, preferably one substituent,
* Indicates a bond between R 1 and a compound according to any of formulas (I) to (III)).
上で概説したR1の好ましい実施形態において、R2がHであることが特に好ましい。 In the preferred embodiment of R 1 outlined above, it is particularly preferred that R 2 is H.
本発明の化合物のさらなる好ましい一実施形態では、R2はHである。 In a further preferred embodiment of the compounds of the present invention, R 2 is H.
以下の表1には、本発明の化合物の特定の置換基のさらに好ましい組合せを列挙しており、表に示されていない残りの置換基は、本明細書に規定される通りである。 Table 1 below lists further preferred combinations of certain substituents of compounds of the present invention, with the remaining substituents not shown in the table being as defined herein.
本発明の化合物の特に好ましい一実施形態では、化合物は、表2及び表3に列挙される化合物の群から選択される。 In one particularly preferred embodiment of the compound of the present invention, the compound is selected from the group of compounds listed in Table 2 and Table 3.
さらなる一態様では、本発明は、疾患又は障害の予防又は治療のための、本発明による化合物、又はその薬学的に許容可能な塩を提供する。 In a further aspect, the present invention provides a compound according to the present invention, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a disease or disorder.
以下の実施例で示されるように、本発明の化合物の有利な特性は、細胞増殖を効果的に阻害するそれらの能力、及びHIF阻害剤としてのそれらの活性を含む。例えば、本発明の化合物が、低酸素条件下でHIFに媒介される転写の活性化を阻害することが示された。したがって、本発明の化合物を、病態生理学的なHIFシグナル伝達を特徴とする障害の治療のための薬物の調製のために使用することができる。医学、生物学及び/又は薬理科学の当業者は、障害が望ましくないHIFシグナル伝達を特徴とするかどうかを、日常的な方法論により決定することができる。このような疾患に罹患した組織は、HIF応答要素(HRE)の活性化により誘導される遺伝子を過剰発現する。HIF−1は、配列NCGTGを一般的に含有するプロモーターにおけるHIF応答要素(HRE)と結合することにより作用する。上記プロモーターにより調節されるHIF活性により影響を受ける遺伝子は当該技術分野で既知であり、複数の概説にも記載された(例えばGregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3の図3を参照されたい)。 As shown in the examples below, the advantageous properties of the compounds of the invention include their ability to effectively inhibit cell proliferation, and their activity as HIF inhibitors. For example, the compounds of the present invention have been shown to inhibit HIF-mediated transcriptional activation under hypoxic conditions. Thus, the compounds of the invention can be used for the preparation of a medicament for the treatment of disorders characterized by pathophysiological HIF signaling. One of ordinary skill in medicine, biology and / or pharmacology can determine by routine methodology whether a disorder is characterized by undesirable HIF signaling. Tissues affected by such diseases overexpress genes induced by activation of HIF response elements (HRE). HIF-1 acts by binding to a HIF response element (HRE) in a promoter that generally contains the sequence NCGTG. Genes affected by HIF activity regulated by the promoter are known in the art and have also been described in several reviews (eg, FIG. 3 of Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3). See).
動物研究において、HIF−1の過剰発現は、腫瘍の成長の増大、血管新生の増大、転移、及び線維症、例えば腎線維症(Semenza, G, Drug Discovery Today, vol. 12, no. 19/20, October 2007、Kimura, Kuniko, et al., American Journal of Physiology (2008), 295(4, Pt. 2), F1023-F1029を参照されたい。概説に関してはN.J. Mabjeesh etal., Histol. Histopathol (2007)22:559-572を参照されたい)と関連する。線維症は、臓器又は組織における過剰な線維結合組織の形成又は発生である。近年、HIF−1活性の阻害が、マクロファージ及び好中球の活性化及び罹患組織中への浸潤におけるその本質的な役割に基づき、炎症を予防するようにも作用することが明らかになった(例えば非特許文献2を参照されたい)。 In animal studies, overexpression of HIF-1 is associated with increased tumor growth, increased angiogenesis, metastasis, and fibrosis such as renal fibrosis (Semenza, G, Drug Discovery Today, vol. 12, no. 19 / 20, October 2007, Kimura, Kuniko, et al., American Journal of Physiology (2008), 295 (4, Pt. 2), F1023-F1029, for review NJ Mabjeesh etal., Histol. Histopathol ( 2007) 22: 559-572). Fibrosis is the formation or development of excess fibrous connective tissue in an organ or tissue. Recently, it has been shown that inhibition of HIF-1 activity also acts to prevent inflammation based on its essential role in macrophage and neutrophil activation and infiltration into diseased tissue ( For example, see Non-Patent Document 2.)
医薬組成物
上で言及した理由のために、本発明の化合物を、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及びまた病態生理学的な過剰血管新生を特徴とする疾患を治療するために使用することができる。したがってさらなる一態様として、本発明は、本発明の化合物を上述の疾患又は障害のうちの1つを治療するのに有用な少なくとも1つのさらなる薬学的に活性な化合物と組み合わせた、治療用組成物を提供する。上記少なくとも1つのさらなる薬学的に活性な化合物の存在により本発明の化合物の治療の有効性を増幅することができる(逆も成立する)ため、このような治療用組成物は有用である。例えば、アンチセンス遺伝子療法を介してHIF1α活性を阻害することにより、肝細胞癌に働く(combat)ドキソルビシンの治療の有効性が増強されることが示された(Liu,Fengjun et. al., Cancer Science (2008), 99(10), 2055-2061を参照されたい)。
Pharmaceutical compositions For the reasons mentioned above, the compounds of the invention are characterized by inflammatory diseases, hyperproliferative or hyperproliferative disorders, hypoxia-related lesions, and also pathophysiological hyperangiogenesis Can be used to treat a disease. Accordingly, in a further aspect, the present invention provides a therapeutic composition comprising a compound of the invention in combination with at least one additional pharmaceutically active compound useful for treating one of the above mentioned diseases or disorders. I will provide a. Such therapeutic compositions are useful because the presence of the at least one additional pharmaceutically active compound can amplify the therapeutic efficacy of the compounds of the invention (and vice versa). For example, inhibition of HIF1α activity via antisense gene therapy has been shown to enhance the efficacy of doxorubicin treatment acting on hepatocellular carcinoma (Liu, Fengjun et. Al., Cancer Science (2008), 99 (10), 2055-2061).
したがってさらなる一態様では、本発明は、本発明による化合物又はその薬学的に許容可能な塩、並びに炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び病態生理学的な過剰血管新生を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防に有用な第2の治療薬、並びに任意に薬学的に許容可能な担体又は賦形剤を含む、医薬組成物に関する。このような組成物は、例えば、相乗的な治療効果を得るのにも、また腫瘍細胞の薬剤抵抗性を防止するのにも有用である。現在の化学療法が概して、治療の有効性を改善するために、及び腫瘍細胞の適応の可能性を低減させるために、異なる細胞傷害化合物及び/又は細胞分裂抑制化合物のカクテル(cocktail)を投与することを伴うのも、これらの理由のためである。 Thus, in a further aspect, the present invention relates to a compound according to the invention or a pharmaceutically acceptable salt thereof, as well as inflammatory diseases, hyperproliferative diseases or hyperproliferative disorders, hypoxia related lesions and pathophysiological excesses. A pharmaceutical composition comprising a second therapeutic agent useful for the treatment or prevention of a disease or disorder selected from the group consisting of diseases characterized by angiogenesis, and optionally a pharmaceutically acceptable carrier or excipient About. Such compositions are useful, for example, for obtaining a synergistic therapeutic effect and for preventing drug resistance of tumor cells. Current chemotherapy generally administers cocktails of different cytotoxic compounds and / or cytostatic compounds in order to improve the effectiveness of treatment and to reduce the likelihood of tumor cell adaptation It is for these reasons that this is accompanied.
さらなる一態様では、本発明は、放射線療法と組み合わせる、本発明による化合物又はその薬学的に許容可能な塩を含む、医薬組成物に関する。 In a further aspect, the invention relates to a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof in combination with radiation therapy.
本発明の任意の組成物を、薬学的に許容可能な希釈剤、賦形剤若しくは担体、又はそれらの混合物と混和することができる。 Any composition of the invention can be admixed with a pharmaceutically acceptable diluent, excipient or carrier, or mixtures thereof.
本発明の化合物(それらの薬学的に許容可能な塩、エステル、及び薬学的に許容可能な溶媒和物を含む)を単独で投与することができるとしても、特にヒトの治療に関しては、薬学的な担体、賦形剤又は希釈剤との混和物として投与されるのが一般的である。医薬組成物は、ヒト医学及び獣医学においてはヒト又は動物への使用のためのものであり得る。本明細書で記載される医薬組成物の様々な異なる形態のためのこのような好適な賦形剤の例は、"Handbook of Pharmaceutical Excipients", 2nd Edition, (1994)(A Wade and PJ Weller編)に見出すことができる。治療用の使用のための許容可能な担体又は希釈剤は薬学分野において既知であり、例えばRemington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro編)(1985)に記載されている。 Even though the compounds of the present invention (including pharmaceutically acceptable salts, esters, and pharmaceutically acceptable solvates thereof) can be administered alone, especially for human therapy, Typically administered as an admixture with a suitable carrier, excipient or diluent. The pharmaceutical composition may be for human or animal use in human and veterinary medicine. Examples of such suitable excipients for various different forms of the pharmaceutical compositions described herein are described in “Handbook of Pharmaceutical Excipients”, 2nd Edition, (1994) (A Wade and PJ Weller ) Can be found. Acceptable carriers or diluents for therapeutic use are known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (Edited by A. R Gennaro) (1985).
本発明の化合物から医薬組成物を調製するために、薬学的に許容可能な担体は、固体又は液体のいずれであってもよい。固体形態の調製物としては、粉末、錠剤、丸薬、カプセル、カシェ剤(cachets)、坐剤及び分散性顆粒が挙げられる。固体担体は、希釈剤、香料、結合剤、保存料、錠剤崩壊剤又は封入材料としても作用し得る、1つ又は複数の物質であり得る。 For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
粉末においては、担体は微粉化した固体であり、微粉化した活性成分との混合物中に存在する。錠剤においては、活性成分は、必要な結合特性を有する担体と好適な比率で混合され、所望の形状及び大きさで圧縮される。 In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compressed in the desired shape and size.
粉末及び錠剤は、好ましくは5%〜80%、より好ましくは20%〜70%の活性化合物(単数又は複数)を含有する。好適な担体は、炭酸マグネシウム、ステアリン酸マグネシウム、タルク、糖、ラクトース、ペクチン、デキストリン、デンプン、ゼラチン、トラガカント、メチルセルロース、カルボキシメチルセルロースナトリウム、低融点ワックス、ココアバター等である。「調製物(preparation)」という用語は、カプセルをもたらす担体としての封入材料を伴う活性化合物の配合物(formulation)を含むことを意図し、該カプセルにおいて活性成分は、他の担体と共に又は他の担体を伴わずに担体に取り囲まれており、そのようにして担体と結合している。同様に、カシェ剤及びトローチ剤が含まれる。錠剤、粉末、カプセル、丸薬、カシェ剤及びトローチ剤を、経口投与に好適な固体投与形態として使用することができる。 Powders and tablets preferably contain 5% to 80% of active compound (s), more preferably 20% to 70%. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with the encapsulating material as a carrier that results in a capsule in which the active ingredient can be combined with other carriers or other It is surrounded by a carrier without a carrier and is thus bonded to the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
坐剤を調製するために、低融点ワックス、例えば脂肪酸グリセリド又はココアバターの混合物を最初に融解し、その中に活性成分を撹拌等により均一に分散させる。その後融解した均一な混合物を、都合の良い大きさの型に注ぎ込み、冷却することにより、固化させる。 For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to solidify by cooling.
液体形態調製物としては、溶液、懸濁液及びエマルション、例えば水又は水/プロピレングリコール溶液が挙げられる。眼への局所適用のためには液体形態が特に好ましい。非経口注入のために、ポリエチレングリコール水溶液の溶液で液体調製物を構築することができる。 Liquid form preparations include solutions, suspensions and emulsions, for example water or water / propylene glycol solutions. The liquid form is particularly preferred for topical application to the eye. For parenteral injection, liquid preparations can be constructed with solutions in aqueous polyethylene glycol solution.
経口使用に好適な水溶液を、活性成分を水に溶解すること、並びに好適な着色料、香料、安定剤及び増粘剤を必要に応じて添加することにより、調製することができる。経口使用に好適な水性懸濁液は、粘性材料(例えば天然又は合成のガム、樹脂、メチルセルロース、カルボキシメチルセルロースナトリウム、及び他の既知の懸濁剤)と共に、微粉化した活性成分を水に分散させることにより、作製することができる。 Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use disperse the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents. Thus, it can be manufactured.
使用直前に経口投与のための液体形態調製物に変換することが意図される固体形態調製物も含まれる。このような液体形態としては、溶液、懸濁液及びエマルションが挙げられる。これらの調製物は、活性成分に加えて、着色料、香料、安定剤、緩衝剤、人工及び天然の甘味料、分散剤、増粘剤、可溶化剤等を含有していてもよい。 Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.
医薬調製物は、好ましくは単位投与形態である。このような形態では調製物は、適当量の活性成分を含有する単位用量へと細分割される(subdivided)。単位投与形態は、包装した調製物であってもよく、該包装は、個別の量の調製物、例えば包装した錠剤、カプセル、及びバイアル又はアンプル中の粉末を含有する。また、単位投与形態は、カプセル、錠剤、カシェ剤若しくはトローチ剤それ自体であってもよく、又は単位投与形態は、適当数の、包装した形態のこれらのいずれかであってもよい。 The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet or troche itself, or the unit dosage form can be any of these in a suitable number of packaged forms.
興味深いことに、HIF阻害剤、例えば本発明の化合物は、化学療法薬剤に対する腫瘍の抵抗性の発達を防止することができると共に、がん細胞を放射線療法に対してより感受性にすることができる(例えばPalayoor ST, et al., Int J Cancer. 2008 Nov 15; 123(10):2430-7及びGregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3を参照されたい)。したがって、本発明の化合物と組み合わせて本発明の医薬組成物を製造することができる有用な第2の治療薬としては、(さらなる)HIF−1阻害剤、細胞傷害化合物及び細胞分裂抑制化合物が挙げられるが、これらに限定されない。 Interestingly, HIF inhibitors, such as the compounds of the invention, can prevent the development of tumor resistance to chemotherapeutic agents and can make cancer cells more sensitive to radiation therapy ( See, for example, Palayoor ST, et al., Int J Cancer. 2008 Nov 15; 123 (10): 2430-7 and Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3). Accordingly, useful second therapeutic agents that can be used in combination with the compounds of the present invention to produce the pharmaceutical compositions of the present invention include (further) HIF-1 inhibitors, cytotoxic compounds and cytostatic compounds. However, it is not limited to these.
HIF−1阻害剤は、例えばPX−478(S−2−アミノ−3−[4'−N,N,−ビス(2−クロロエチル)アミノ]フェニルプロピオン酸N−オキシド二塩酸塩);トポイソメラーゼ−1阻害剤、例えば8,9−ジメトキシ−5−(2−N,N−ジメチルアミノエチル)−2,3−メチレンジオキシ−5H−ジベンゾ[c,h][1,6]ナフチリジン−6−オン(ARC−111又はトポベイル(topovale)としても知られる)又は(S)−10−[(ジメチルアミノ)メチル]−4−エチル−4,9−ジヒドロキシ−1H−ピラノ[3’,4’:6,7]インドリジノ[1,2−b]キノリン−3,14−(4H,12H)−ジオン一塩酸塩(トロポテカン(tropotecan)とも称される);エキノマイシン;ケトミン(NSC289491);シクロスポリンA;3−[2−[4−[ビス(4−フルオロフェニル)メチレン]−1−ピペリジニル]−2,3−ジヒドロ−2−チオキソ−4(1H)−キナゾリノン(R59949);PIK3K/Akt/mTorシグナル伝達カスケードの阻害剤、例えばLY294002、ウォルトマニン又はラパマイシン;MAPKシグナル伝達カスケードの阻害剤、例えばMEK1阻害剤(PD98059);可溶性グアニルシクラーゼ刺激因子、例えば3−(5’−ヒドロキシメチル−2’−フリル)−1−ベンジルインダゾール(YC−1);熱ショックタンパク質90阻害剤、特にラディシコール、ラディシコール類似体(KF58333)又はゲルダナマイシン;微小管破壊剤、特に例えばタキソール、ビンクリスチン又は2−メトキシエストラジオール;ヒストンデアセチラーゼ阻害剤、例えばFK228;チオレドキシン阻害剤、特にPX−12又はプレウロチン(pleurotin);UCNO−1;ジフェニレンヨードニウム、ゲネステイン及びカルボキシアミド−トリアゾールからなる群から選択することができる。 HIF-1 inhibitors include, for example, PX-478 (S-2-amino-3- [4′-N, N, -bis (2-chloroethyl) amino] phenylpropionic acid N-oxide dihydrochloride); topoisomerase- 1 inhibitor, such as 8,9-dimethoxy-5- (2-N, N-dimethylaminoethyl) -2,3-methylenedioxy-5H-dibenzo [c, h] [1,6] naphthyridine-6 On (also known as ARC-111 or topovale) or (S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyrano [3 ′, 4 ′: 6,7] Indolizino [1,2-b] quinoline-3,14- (4H, 12H) -dione monohydrochloride (also referred to as tropotecan); echinomycin; ketomin (NSC 289491) Cyclosporin A; 3- [2- [4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] -2,3-dihydro-2-thioxo-4 (1H) -quinazolinone (R59949); PIK3K / Inhibitors of the Akt / mTo signaling cascade, such as LY294002, wortmannin or rapamycin; inhibitors of the MAPK signaling cascade, such as MEK1 inhibitor (PD98059); soluble guanyl cyclase stimulators, such as 3- (5′-hydroxymethyl- 2′-furyl) -1-benzylindazole (YC-1); heat shock protein 90 inhibitors, especially radicicol, radicicol analog (KF58333) or geldanamycin; microtubule disrupting agents, especially eg taxol, vincristine or 2-Met Xiestradiol; a histone deacetylase inhibitor such as FK228; a thioredoxin inhibitor, particularly PX-12 or pleurotin; UCNO-1; can be selected from the group consisting of diphenyleneiodonium, genesteine and carboxamide-triazole .
多くの細胞傷害化合物又は細胞分裂抑制化合物が、過剰増殖性疾患又は過剰増殖性障害、例えば腫瘍疾患又はがん疾患の治療に精通した当業者にとって既知である。例えば、細胞傷害化合物及び細胞分裂抑制化合物としては、純粋な又は混合の抗エストロゲン薬、例えばファスロデックス(faslodex)、タモキシフェン又はラロキシフェン;トポイソメラーゼI又はIIの任意の阻害剤、例えばカンプトテシン(topo I)又はエトポシド(topo II);アロマターゼ活性を阻害することにより作用する任意の化合物、例えばアナストロゾール又はレトロゾール;HER2シグナル伝達を妨げる任意の調製物、例えばハーセプチン;DNAに挿入される(interchelates)任意の化合物、例えばドキソルビシンが挙げられるがこれらに限定されない。本発明の化合物と併用することができる特に好ましい細胞分裂抑制薬又は細胞傷害薬は、アルキル化物質、抗代謝剤、抗生物質、エポチロン、核内受容体アゴニスト及びアンタゴニスト、抗アンドロゲン薬、抗エストロゲン薬、白金化合物、ホルモン及び抗ホルモン薬、インターフェロン、及び細胞周期依存性タンパク質キナーゼ(CDK)の阻害剤、シクロオキシゲナーゼ及び/又はリポキシゲナーゼの阻害剤、生体(biogeneic)脂肪酸及び脂肪酸誘導体、例えばプロスタノイド及びロイコトリエン、タンパク質キナーゼの阻害剤、タンパク質ホスファターゼの阻害剤、脂質キナーゼの阻害剤、白金配位錯体、エチレンイミン(ethyleneimenes)、メチルメラミン、トラジン(trazines)、ビンカアルカロイド、ピリミジン類似体、プリン類似体、アルキルスルホネート、葉酸類似体、アントラセンジオン、置換尿素、メチルヒドラジン誘導体、特にアセジアスルホン(acediasulfone)、アクラルビシン(aclarubicine)、アンバゾン、アミノグルテチミド、L−アスパラギナーゼ、アザチオプリン、ブレオマイシン、ブスルファン、ホリネートカルシウム、カルボプラチン、カペシタビン(carpecitabine)、カルムスチン、セレコキシブ、クロラムブシル、シスプラチン、クラドリビン、シクロホスファミド、シタラビン、ダカルバジン、ダクチノマイシン、ダプソン、ダウノルビシン、ジブロムプロパミジン、ジエチルスチルベストロール(diethylstilbestrole)、ドセタキセル、ドキソルビシン、エンジイン、エピルビシン、エポチロンB、エポチロンD、リン酸エストラムスチン(estramucinphosphate)、エストロゲン、エチニルエストラジオール(ethinylestradiole)、エトポシド、フラボピリドール、フロクスウリジン、フルダラビン、フルオロウラシル、フルオキシメステロン、フルタミド、ホスフェストロール、フラゾリドン、ゲムシタビン、ゴナドトロピン放出ホルモン類似体、ヘキサメチルメラミン、ヒドロキシカルバミド、ヒドロキシメチルニトロフラントイン、ヒドロキシプロゲステロンカプロエート(hydroxyprogesteronecaproat)、ヒドロキシ尿素、イダルビシン、イドクスウリジン、イホスファミド、インターフェロンγ、イリノテカン、ロイプロリド、ロムスチン、ラルトテカン(lurtotecan)、マフェニドスルフェートオラミド(mafenide sulfate olamide)、メクロレタミン、酢酸メドロキシプロゲステロン、酢酸メゲストロール(megastrolacetate)、メルファラン、メパクリン、メルカプトプリン、メトトレキサート、メトロニダゾール、ミトマイシンC、ミトポドジド、ミトタン、ミトキサントロン、ミトラマイシン、ナリジクス酸、ニフラテル、ニフロキサジド、ニフララジン(nifuralazine)、ニフルチモックス、ニムスチン、ニモラゾール(ninorazole)、ニトロフラントイン、ナイトロジェンマスタード、オレオムシン(oleomucin)、オキソリニン酸、ペンタミジン、ペントスタチン、フェナゾピリジン、フタリルスルファチアゾール、ピポブロマン、プレドニムスチン、プレドニゾン、プレウシン(preussin)、プロカルバジン、ピリメタミン、ラルチトレキセド、ラパマイシン、ロフェコキシブ、ロシグリタゾン、サラゾスルファピリジン、塩化アクリフラビニウム(scriflaviniumchloride)、セムスチン、ストレプトゾシン(streptozocine)、スルファカルバミド、スルファセタミド、スルファクロルピリダジン(sulfachlopyridazine)、スルファジアジン、スルファジクラミド、スルファジメトキシン、スルファエチドール、スルファフラゾール、スルファグアニジン、スルファグアノール、スルファメチゾール、スルファメトキサゾール、コトリモキサゾール、スルファメトキシジアジン、スルファメトキシピリダジン、スルファモキソール、スルファニルアミド、スルファペリン、スルファフェナゾール、スルファチアゾール、スルフイソミジン、スタウロスポリン、タモキシフェン、タキソール、テニポシド、ターチポシド(tertiposide)、テストラクトン、プロピオン酸テストステロン(testosteronpropionate)、チオグアニン、チオテパ、チニダゾール、トポテカン、トリアジコン、トレオスルファン、トリメトプリム、トロホスファミド、UCN−01、ビンブラスチン、ビンクリスチン、ビンデシン、ビンブラスチン、ビノレルビン、及びゾルビシン、又はそのそれぞれの誘導体若しくは類似体である。上で示した薬剤の幾つかは、ここではがん療法のために同時に投与されるので、2つ以上の細胞分裂抑制薬及び/又は細胞傷害薬が本発明の組成物中に含まれ得ることも想定される。 Many cytotoxic or cytostatic compounds are known to those skilled in the art for treating hyperproliferative or hyperproliferative disorders, such as tumor diseases or cancer diseases. For example, cytotoxic and cytostatic compounds include pure or mixed antiestrogens such as faslodex, tamoxifen or raloxifene; any inhibitor of topoisomerase I or II such as camptothecin (topo I) Or etoposide (topo II); any compound that acts by inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signaling, such as Herceptin; any that is interchelates And, for example, doxorubicin, but are not limited thereto. Particularly preferred cytostatic or cytotoxic agents that can be used in combination with the compounds of the present invention are alkylating substances, antimetabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, antiandrogens, antiestrogens Platinum compounds, hormones and antihormonal drugs, interferons, inhibitors of cell cycle dependent protein kinases (CDK), inhibitors of cyclooxygenase and / or lipoxygenase, biogeneic fatty acids and fatty acid derivatives such as prostanoids and leukotrienes, Protein kinase inhibitors, protein phosphatase inhibitors, lipid kinase inhibitors, platinum coordination complexes, ethyleneimines, methylmelamine, trazines, vinca alkaloids, pyrimidine analogues, purine analogues, a Rukyrusulfonate, folic acid analogue, anthracenedione, substituted urea, methylhydrazine derivatives, especially acediasulfone, aclarubicine, abazone, aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, folinate calcium , Carboplatin, capecitabine (carpecitabine), carmustine, celecoxib, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetiltataxel Doxorubicin, enediyne, epirubicin, epothilone B, epothilone D, estramucinphosphate phosphate, Estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, phosfestol, furazolidone, gemcitabine, gonadotropin-releasing hormone analog, hexamethylmelamine, hydroxycarbamide, Hydroxymethylnitrofurantoin, hydroxyprogesteronecaproate, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon gamma, irinotecan, leuprolide, lomustine, rartotecan, mafenide sulfate oramide (mafenide sulfate) olamide), mechloretamine, medroxyprogesterone acetate, megestrol acetate (megastrolacetat) e), melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mitramycin, nalidixic acid, niflater, nifloxazide, nifuralazine, nifurtimox, nimustine, azole ), Nitrofurantoin, nitrogen mustard, oleomucin, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalyl sulfathiazole, piprobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, rapamycin , Rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride ), Semustine, Streptozocine, Sulfacarbamide, Sulfacetamide, Sulfachlorpyridazine, Sulphadiazine, Sulfadiclamide, Sulfadimethoxine, Sulfaethidol, Sulfafurazole, Sulfaguanidine, Sulfaguanol Sulfamethizole, sulfamethoxazole, cotrimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxol, sulfanilamide, sulfaperine, sulfaphenazole, sulfathiazole, sulfisomidine, Taurosporine, tamoxifen, taxol, teniposide, tertiposide, test lactone, testosteron propionate, thioguanine, thiote Pa, tinidazole, topotecan, triadicon, treosulphan, trimethoprim, trophosphamide, UCN-01, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their respective derivatives or analogues. Since some of the agents shown above are administered simultaneously here for cancer therapy, more than one cytostatic and / or cytotoxic agent may be included in the composition of the present invention. Is also envisaged.
上で言及したように、HIF阻害剤はがん細胞を化学療法及び放射線療法に対してより脆弱にする。したがって、過剰増殖性疾患又は過剰増殖性障害を効果的に治療するために、本発明の化合物を他の活性な薬剤(medicinal agents)と同時に投与することができ、及び/又は他の抗がん療法、抗腫瘍療法若しくは抗増殖性疾患療法と併せて投与することができる。一態様では、本発明は、過剰増殖性疾患又は過剰増殖性障害を治療する方法であって、放射線療法、化学療法、免疫療法、レーザー/マイクロ波温熱療法、又はアンチセンスDNA及びRNAを使用する遺伝子療法(例えばMoeller et al., Cancer Cell 2004 5429-441を参照されたい)を患者が受ける前に、受ける間に、及び/又は受けた後に、上記患者に対して本発明による化合物を投与することを含む、方法を提供する。 As mentioned above, HIF inhibitors make cancer cells more vulnerable to chemotherapy and radiation therapy. Thus, in order to effectively treat hyperproliferative diseases or hyperproliferative disorders, the compounds of the invention can be administered concurrently with other active agents and / or other anti-cancers It can be administered in conjunction with therapy, antitumor therapy or antiproliferative disease therapy. In one aspect, the invention is a method of treating a hyperproliferative disease or disorder, using radiation therapy, chemotherapy, immunotherapy, laser / microwave thermotherapy, or antisense DNA and RNA. Administration of a compound according to the invention to said patient before, during and / or after receiving gene therapy (see eg Moeller et al., Cancer Cell 2004 5429-441) To provide a method.
さらなる一態様では、本発明は、既に上で概説したように、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、例えば糖尿病性網膜症、虚血性再かん流傷害、虚血性心筋四肢疾患(ischemic myocardial and limb disease)、虚血性脳卒中、敗血症及び敗血性ショック(例えばLiu FQ, et al., Exp Cell Res. 2008 Apr 1;314(6): 1327-36を参照されたい);並びに病態生理学的な過剰血管新生を特徴とする疾患、例えば骨肉腫における血管形成(例えばYang, Qing-cheng et al., Dier Junyi Daxue Xuebao(2008), 29(5),504-508を参照されたい)、黄斑変性、特に加齢性黄斑変性及び血管増殖性網膜症(例えばKim JH, etal., J Cell Mol Med. 2008 Jan 19を参照されたい)からなる群から選択される疾患又は障害の治療又は予防のための薬物の調製のための本発明による化合物又は本発明による組成物の使用を提供する。 In a further aspect, the invention relates to inflammatory diseases, hyperproliferative diseases or hyperproliferative disorders, hypoxia related lesions such as diabetic retinopathy, ischemic reperfusion injury, imaginary, as already outlined above. See ischemic myocardial and limb disease, ischemic stroke, sepsis and septic shock (see, eg, Liu FQ, et al., Exp Cell Res. 2008 Apr 1; 314 (6): 1327-36 As well as diseases characterized by pathophysiological hyperangiogenesis such as angiogenesis in osteosarcoma (eg Yang, Qing-cheng et al., Dier Junyi Daxue Xuebao (2008), 29 (5), 504-508) A disease selected from the group consisting of macular degeneration, in particular age-related macular degeneration and vascular proliferative retinopathy (see for example Kim JH, etal., J Cell Mol Med. 2008 Jan 19) or A compound according to the invention for the preparation of a medicament for the treatment or prevention of a disorder or according to the invention It provides for the use of the composition.
既に上で言及したように、HIF阻害剤、例えば本発明の化合物は炎症性疾患又は炎症性障害を治療するのに有用である。例えば、酸素依存性HIFアイソフォームが乾癬皮膚で強く上方調節されることが示された(例えばRosenberger C, et al., J Invest Dermatol. 2007 Oct; 127(10):2445-52を参照されたい)。さらにHIF阻害剤、ネオバスタット(neovastat)が喘息における気道炎症を阻害することが示された(例えばLee SY,et al., Vascul Pharmacol. 2007 Nov-Dec; 47(5-6):313-8を参照されたい)。さらに、最近の証拠により、HIFが低酸素条件下での関節リウマチにおける関節の炎症及び破壊に関与することも示されている(例えば、Ahn, J. K., et al., Rheumatology(Oxford, UnitedKingdom)(2008), 47(6), 834-839を参照されたい)。したがって、本発明の使用の好ましい一実施形態では、炎症性疾患は、アテローム動脈硬化症、関節リウマチ、喘息、炎症性腸疾患、乾癬、特に尋常性乾癬、頭部乾癬(psoriasis capitis)、滴状乾癬、屈側性乾癬(psoriasis inversa);神経皮膚炎;魚鱗癬(ichtyosises);円形脱毛症;全頭脱毛症;亜全頭脱毛症(alopeciasubtotalis);全身脱毛症;びまん性脱毛症(alopecia diffusa);アトピー性皮膚炎;皮膚の紅斑性狼瘡;皮膚の皮膚筋炎;アトピー性湿疹;モルヘア;強皮症;蛇行型円形脱毛症;アンドロゲン性脱毛症;アレルギー性皮膚炎;刺激性接触皮膚炎;接触皮膚炎;尋常性天疱瘡;落葉状天疱瘡;増殖性天疱瘡;瘢痕性粘膜類天疱瘡;水疱性類天疱瘡;粘膜類天疱瘡;皮膚炎;ジューリング疱疹状皮膚炎;じんま疹;リポイド類壊死症;結節性紅斑;単純性痒疹;結節性痒疹;急性痒疹;リニアIgA皮膚症;多形性光皮膚症;日光性紅斑;皮膚の発疹;薬疹;慢性進行性紫斑;異汗性湿疹(dihydroticeczema);湿疹;固定薬疹;光アレルギー性皮膚反応;及び口囲皮膚炎(perioraledermatitis)からなる群から選択される。したがって、本発明のさらなる好ましい一実施形態は、1つ又は複数の本発明の化合物とこのような炎症性疾患又は炎症性病態を治療するのに現在使用されている薬物療法(medication)との組合せを包含し、この組合せは薬理科学分野の当業者により決定することができる。組合せに関するこのような治療法は、例えば抗炎症性ステロイド、抗酸化剤、炎症プロセスと関連する或る特定のサイトカイン若しくは細胞エピトープを捕捉する若しくはこれらと結合する治療抗体若しくは融合タンパク質、又はメトトレキサートのようなジヒドロ葉酸還元酵素阻害剤の群から選択することができる。 As already mentioned above, HIF inhibitors, such as the compounds of the present invention, are useful for treating inflammatory diseases or disorders. For example, oxygen-dependent HIF isoforms have been shown to be strongly upregulated in psoriatic skin (see, eg, Rosenberger C, et al., J Invest Dermatol. 2007 Oct; 127 (10): 2445-52 ). In addition, the HIF inhibitor neovastat has been shown to inhibit airway inflammation in asthma (eg Lee SY, et al., Vascul Pharmacol. 2007 Nov-Dec; 47 (5-6): 313-8 See). In addition, recent evidence indicates that HIF is involved in joint inflammation and destruction in rheumatoid arthritis under hypoxic conditions (eg, Ahn, JK, et al., Rheumatology (Oxford, UnitedKingdom) ( 2008), 47 (6), 834-839). Thus, in a preferred embodiment of the use of the invention, the inflammatory disease is atherosclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease, psoriasis, especially psoriasis vulgaris, psoriasis capitis, drop-like Psoriasis, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata; global alopecia; subtotal alopecia (alopeciasubtotalis); systemic alopecia; diffuse alopecia (alopecia diffusa) ); Atopic dermatitis; erythematous lupus of the skin; dermatomyositis of the skin; atopic eczema; molehair; scleroderma; serpentine alopecia areata; androgenic alopecia; allergic dermatitis; Contact dermatitis; pemphigus vulgaris; deciduous pemphigus; proliferative pemphigus; scarred mucocele pemphigus; bullous pemphigoid; mucocele pemphigoid; dermatitis; Lipoid necrosis; nodule Eruptive erythema; simple eruption; nodular eruption; acute rash; linear IgA dermatosis; polymorphic photodermatosis; erythema erythema; skin rash; drug eruption; chronic progressive purpura; dihydroticeczema; Selected from the group consisting of eczema; fixed drug eruption; photoallergic skin reaction; and perioraledermatitis. Accordingly, a further preferred embodiment of the present invention provides a combination of one or more compounds of the present invention and a drug therapy currently used to treat such inflammatory diseases or conditions. This combination can be determined by one skilled in the art of pharmacology. Such therapies for combinations include, for example, anti-inflammatory steroids, antioxidants, therapeutic antibodies or fusion proteins that capture or bind to certain cytokines or cellular epitopes associated with inflammatory processes, or methotrexate. Can be selected from the group of dihydrofolate reductase inhibitors.
本発明の化合物は抗増殖効果を示す。さらに、HIF阻害剤、例えば本発明の化合物は、様々ながん疾患の治療に効果的な薬物である(例えばGregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3による総説、及びまたN.J. Mabjeesh et al., Histol. Histopathol(2007), 22:559-572による総説を参照されたい)。したがって、過剰増殖性疾患が腫瘍疾患又はがん疾患、前癌状態、異形成、組織球増殖症、血管増殖性疾患、及びウイルス誘導性増殖性疾患からなる群から選択される、本発明の使用も好ましい。したがって、本発明の使用の好ましい一実施形態では、過剰増殖性疾患は、びまん性大細胞型B細胞リンパ腫(DLBCL)、T細胞リンパ腫又は白血病、例えば皮膚T細胞リンパ腫(CTCL)、非皮膚末梢T細胞リンパ腫、ヒトT細胞リンパ球向性ウイルス(HTLV)と関連するリンパ腫、成人T細胞白血病/リンパ腫(ATLL)、及び急性リンパ性白血病、急性非リンパ性白血病、急性骨髄球性白血病(acute myeloid leukemia)、慢性リンパ性白血病、慢性骨髄性白血病(chronicmyelogenous leukemia)、ホジキン病、非ホジキンリンパ腫、骨髄腫、多発性骨髄腫、中皮腫、小児固形腫瘍、神経膠腫、骨がん及び軟部組織肉腫、成人の一般的な固形腫瘍、例えば頭頚部がん(例えば口腔がん、喉頭がん及び食道がん)、尿生殖器がん(例えば前立腺がん、膀胱がん、腎(renal)がん(特に悪性の腎細胞癌(RCC))、子宮がん、卵巣がん、精巣がん、直腸がん及び結腸がん)、肺がん(例えば小細胞癌及び非小細胞肺癌、例えば扁平上皮癌及び腺癌)、乳がん、膵臓がん、黒色腫及び他の皮膚がん、基底細胞癌、転移性皮膚癌、潰瘍型及び乳頭型の両方の扁平上皮癌、胃がん、脳がん、肝臓がん、副腎(adrenal)がん、腎臓(kidney)がん、甲状腺がん、髄様癌、骨肉腫(osteosarcoma)、軟部組織肉腫、ユーイング肉腫、細網肉腫(veticulum cell sarcoma)、及びカポジ肉腫、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫(osteogenic sarcoma)、脊索腫、血管肉腫、内皮肉腫(endotheliosarcoma)、リンパ管肉腫、リンパ管内皮肉腫(lymphangioendotheliosarcoma)、滑膜腫、中皮腫、平滑筋肉腫、横紋筋肉腫、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、髄様癌、気管支原性癌、精上皮腫、胚性癌、ウイルムス腫瘍、小細胞肺癌、上皮癌、星状細胞腫、髄芽腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽細胞腫、聴神経腫瘍、乏突起神経膠腫、髄膜腫、神経芽腫、網膜芽細胞腫、緑内障、血管腫、重鎖病並びに転移からなる群から選択される腫瘍疾患又はがん疾患である。 The compounds of the present invention exhibit an antiproliferative effect. In addition, HIF inhibitors, such as the compounds of the present invention, are effective drugs for the treatment of various cancer diseases (eg, reviews by Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3, and also NJ (See review by Mabjeesh et al., Histol. Histopathol (2007), 22: 559-572). Thus, the use of the present invention wherein the hyperproliferative disease is selected from the group consisting of tumor disease or cancer disease, precancerous condition, dysplasia, histiocytosis, vascular proliferative disease, and virus-induced proliferative disease Is also preferable. Thus, in a preferred embodiment of the use of the present invention, the hyperproliferative disease is diffuse large B cell lymphoma (DLBCL), T cell lymphoma or leukemia such as cutaneous T cell lymphoma (CTCL), non-cutaneous peripheral T Cell lymphoma, lymphoma associated with human T cell lymphotropic virus (HTLV), adult T cell leukemia / lymphoma (ATLL), and acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia ), Chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumor, glioma, bone cancer and soft tissue sarcoma General solid tumors in adults, such as head and neck cancer (eg, oral, laryngeal and esophageal cancer), urogenital cancer (eg, prostate) Adenocarcinoma, bladder cancer, renal cancer (especially malignant renal cell carcinoma (RCC)), uterine cancer, ovarian cancer, testicular cancer, rectal cancer and colon cancer), lung cancer (eg Small cell and non-small cell lung cancer (eg, squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell cancer, metastatic skin cancer, both ulcer type and papillary type Squamous cell carcinoma, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary cancer, osteosarcoma, soft tissue sarcoma, Ewing sarcoma, fine Veticulum cell sarcoma, and Kaposi sarcoma, fibrosarcoma, mucous sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymph Lymphangioendotheliosarcoma, synovial, mesothelioma, leiomyosarcoma, rhabdomyo Sarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, seminoma, embryonic carcinoma, Wilms tumor, Small cell lung cancer, epithelial cancer, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, It is a tumor disease or cancer disease selected from the group consisting of retinoblastoma, glaucoma, hemangioma, heavy chain disease and metastasis.
本発明の化合物により治療可能な前癌状態は好ましくは、皮膚の前癌状態、特に光線角化症、皮角(cutaneaous horn)、光線口唇炎、タール角化症、ヒ素角化症、X線角化症、ボーエン病、ボーエン様丘疹症、悪性黒子、硬化性苔癬及び粘膜紅色苔癬(lichen rubbermucosae);消化管の前癌状態、特に紅板症、白板症、バレット食道、プランマー・ヴィンソン症候群、下腿潰瘍(crural ulcer)、巨大肥厚性胃炎(gastropathiahypertrophica gigantea)、境界型癌(borderline carcinoma)、新生物性腸ポリープ、直腸ポリープ、陶器様胆嚢;婦人科前癌状態、特に乳管上皮内癌(carcinomaductale in situ)(CDIS)、子宮頚部上皮内腫瘍(CIN)、白板症、子宮内膜増殖症(グレードIII)、外陰ジストロフィー、外陰上皮内腫瘍(VIN)、胞状奇胎;泌尿器前癌状態、特に膀胱乳頭腫、ケイラー赤色肥厚症、精巣上皮内腫瘍(TIN)、白板症;上皮内癌(CIS);慢性炎症により引き起こされる前癌状態、特に膿皮症、骨髄炎、集簇性ざ瘡、尋常性狼瘡及び瘻孔からなる群から選択される。 Precancerous conditions treatable by the compounds of the present invention are preferably precancerous conditions of the skin, in particular photokeratosis, cutaneaous horn, photo cheilitis, tar keratosis, arsenic keratosis, X-ray Keratosis, Bowen's disease, Bowen-like papulosis, malignant mole, sclerotic lichen, and lichen rubbermucosae; precancerous conditions of the gastrointestinal tract, especially erythroderma, leukoplakia, Barrett's esophagus, plumer Vinson syndrome, crural ulcer, giant hypertrophic gastritis (gastropathiahypertrophica gigantea), borderline carcinoma, neoplastic intestinal polyp, rectal polyp, pottery-like gallbladder; gynecological precancerous condition, especially ductal epithelium Carcinomaductale in situ (CDIS), cervical intraepithelial neoplasia (CIN), leukoplakia, endometrial hyperplasia (grade III), vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), hydatidiform mole; pre-urinary Cancerous condition , Especially bladder papilloma, Kayler red hypertrophy, testicular intraepithelial neoplasia (TIN), leukoplakia; carcinoma in situ (CIS); precancerous conditions caused by chronic inflammation, especially pyoderma, osteomyelitis, confluent Selected from the group consisting of acne, acne vulgaris and fistula.
異形成はがんの前兆であることが多く、例えば上皮中に見出され得る。異形成は非新生物性細胞成長の最も無秩序な形態であり、個々の細胞の均一性、及び細胞の構造的配向(architectural orientation)の喪失を伴う。異形成細胞は多くの場合、異常に大きな濃く染まった核を有し、多形性を示す。異形成は、慢性の刺激又は炎症が存在する場所で発生することを特徴とする。本発明の化合物により治療することができる異形成障害としては、無汗性外胚葉異形成、前後異形成、窒息性胸郭異形成、心房指異形成(atriodigital dysplasia)、気管支肺異形成、脳異形成、子宮頚部異形成、軟骨外胚葉異形成、鎖骨頭蓋異形成、先天性外胚葉異形成、頭蓋骨幹異形成、頭蓋手根足根骨異形成、頭蓋骨幹端異形成、象牙質異形成、骨幹異形成、外胚葉異形成、エナメル質異形成、脳眼異形成、半肢骨端異形成(dysplasiaepiphysialis heminelia)、多発性骨端異形成、点状骨端異形成(dysplasia epiphysalis punctata)、上皮異形成、顔面指趾生殖器異形成、下顎の家族性線維性異形成、家族性白色襞性異形成、線維筋性異形成、線維性骨異形成、開花性骨異形成、遺伝性腎−網膜異形成、発汗性外胚葉異形成、発汗減少症性外胚葉異形成、リンパ球減少性胸腺異形成、乳腺異形成、下顎顔面異形成、骨幹端異形成(metaphysicaldysplasia)、モンディーニ型内耳異形成、単骨性線維性骨異形成、粘膜上皮異形成、多発性骨端異形成、眼耳脊椎異形成、眼歯指異形成、眼脊椎異形成、歯原性異形成、眼下顎四肢異形成、根尖性セメント質異形成、多発性線維性骨異形成、偽軟骨発育不全脊椎骨端異形成、網膜異形成、中隔視神経異形成、脊椎骨端異形成、及び心室橈骨異形成が挙げられるがこれらに限定されない。 Dysplasia is often a precursor to cancer and can be found, for example, in the epithelium. Dysplasia is the most disordered form of non-neoplastic cell growth and involves loss of individual cell homogeneity and cellular architectural orientation. Dysplastic cells often have abnormally large darkly stained nuclei and are polymorphic. Dysplasia is characterized by occurring where chronic irritation or inflammation is present. The dysplasia disorders that can be treated with the compounds of the present invention include non-hidrotic ectoderm dysplasia, anteroposterior dysplasia, asphyxia thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, brain dysplasia Formation, cervical dysplasia, cartilage ectodermal dysplasia, clavicular skull dysplasia, congenital ectodermal dysplasia, skull stem dysplasia, skull carpal-tarsal dysplasia, skull metaphyseal dysplasia, dentin dysplasia, Dysplasia epiphysalis punctata, dysplasia epiphysalis punctata, dysplasia epiphysialis heminelia, multiple epiphyseal dysplasia, dysplasia epiphysalis punctata, epithelium Dysplasia, facial finger genital dysplasia, familial fibrous dysplasia of the lower jaw, familial white dysplasia, fibromuscular dysplasia, fibrous bone dysplasia, flowering bone dysplasia, hereditary kidney-retina Dysplasia, sweating ectoderm dysplasia, hypohidrosis ectoderm dysplasia, phosphorus Cytopenic thymic dysplasia, mammary dysplasia, mandibular facial dysplasia, metaphysical dysplasia, Mondini-type inner ear dysplasia, single bone fibrous dysplasia, mucosal epithelial dysplasia, multiple epiphyseal dysplasia Formation, ocular-ear spinal dysplasia, odontoid dysplasia, ocular spinal dysplasia, odontogenic dysplasia, ocular mandibular limb dysplasia, apical cementum dysplasia, multiple fibrous bone dysplasia, pseudochondral development Examples include, but are not limited to, dysplastic vertebral dysplasia, retinal dysplasia, septal optic dysplasia, vertebral epiphyseal dysplasia, and ventricular rib dysplasia.
エストロゲン受容体は、ホルモン17β−エストラジオール(エストロゲン)により活性化される受容体群を表す。2つのタイプのエストロゲン受容体が存在する:細胞内受容体の核ホルモンファミリーの成員であるER、及びGタンパク質共役受容体であるエストロゲンGタンパク質共役受容体GPR30(GPER)。エストロゲン及びエストロゲン受容体は、乳がん、卵巣がん、結腸がん、前立腺がん及び子宮内膜がん、並びに他の疾患に関与している。本発明の化合物はエストロゲン受容体に媒介される転写活性を阻害することができるため、上記疾患を治療するのに使用することができる。 Estrogen receptors represent a group of receptors that are activated by the hormone 17β-estradiol (estrogens). There are two types of estrogen receptors: ER, a member of the nuclear hormone family of intracellular receptors, and estrogen G protein coupled receptor GPR30 (GPER), a G protein coupled receptor. Estrogens and estrogen receptors are implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer and endometrial cancer, and other diseases. The compounds of the present invention can inhibit estrogen receptor-mediated transcriptional activity and therefore can be used to treat the above diseases.
したがって、さらなる好ましい一実施形態では、本発明に従って治療可能な過剰増殖性障害は、エストロゲン受容体シグナル伝達を低減させることによる利益を受ける障害、すなわち健常な組織と比較して増大したエストロゲン受容体シグナル伝達と関連する障害である。本発明の化合物のこの特定の適合性は、潜在的に細胞複製を阻害することを通じて、また可能性としては本発明の化合物の付加的な活性を通して、本発明の化合物がエストロゲン受容体シグナル伝達の阻害をもたらすという事実に基づいている。したがって、治療することのできる好ましい疾患、病態及び/又は障害は、乳腫瘍、子宮内膜腫瘍及び子宮の腫瘍からなる群から選択される。疾患がエストロゲン受容体活性の増大と関連するか否かは、以下の実験部でより詳細に説明されるように、様々な当該技術分野で既知の方法、例えば、発現タンパク質の量を決定する例えば免疫学的方法による疾患組織におけるER発現レベルの決定により、転写ERをコードする核酸の量を決定する方法、例えばRT−PCR、ノーザンブロット法、核ランオン(nuclear run-ons)等により、及び検出可能なレポーター、例えばCAT、ルシフェラーゼ、GFP等の発現を駆動するER受容体認識要素を含む核酸構築物の活性を決定する方法により、測定することができる。好ましくは、エストロゲン受容体シグナル伝達を低減させることによる利益を受ける障害は、健常な組織と比較して疾患組織(tisse)で少なくとも10%、好ましくは少なくとも20%、30%、40%、50%、60%、70%のエストロゲン受容体シグナル伝達の増大を示す障害である。好ましくはこの増大は、ER受容体認識要素を含む核酸、及びこの要素により駆動されたレポーターの発現の増大に基づき測定する。 Thus, in a further preferred embodiment, a hyperproliferative disorder treatable according to the present invention is a disorder that benefits from reducing estrogen receptor signaling, i.e. an increased estrogen receptor signal compared to healthy tissue. Disability associated with transmission. This particular suitability of the compounds of the present invention is that the compounds of the present invention are capable of estrogen receptor signaling through potentially inhibiting cell replication and possibly through the additional activity of the compounds of the present invention. Based on the fact that it causes inhibition. Accordingly, preferred diseases, conditions and / or disorders that can be treated are selected from the group consisting of breast tumors, endometrial tumors and uterine tumors. Whether the disease is associated with increased estrogen receptor activity is determined by various art-known methods, e.g., determining the amount of expressed protein, as described in more detail in the experimental section below. By determining the level of ER expression in diseased tissues by immunological methods, by determining the amount of nucleic acid encoding transcribed ER, eg by RT-PCR, Northern blot, nuclear run-ons, and detection It can be measured by methods that determine the activity of nucleic acid constructs containing ER receptor recognition elements that drive expression of possible reporters such as CAT, luciferase, GFP, and the like. Preferably, the disorder that benefits from reducing estrogen receptor signaling is at least 10%, preferably at least 20%, 30%, 40%, 50% in diseased tissue compared to healthy tissue. , 60%, 70% disorder showing increased estrogen receptor signaling. Preferably, this increase is measured based on increased expression of a nucleic acid comprising an ER receptor recognition element and a reporter driven by this element.
細胞複製の阻害を通して作用する、エストロゲン受容体シグナル伝達のアンタゴニストとしての治療的使用では、本発明の使用に利用される化合物を1日約0.02mg/kg〜約20mg/kgの初期投与量で投与する。約0.05mg/kg〜約2mg/kgの1日用量範囲が好ましく、約0.05mg/kg〜約1mg/kgの1日用量範囲が最も好ましい。しかしながら、投与量は患者の要求、治療される病態の重症度、及び利用される化合物に応じて変わり得る。特定の状況に関する適切な投与量の決定は実務家(practitioner)の技能の範囲内である。一般的には、治療は化合物の最適用量未満のより少ない投与量で開始する。その後、環境下で最適な効果が達成されるまで、投与量を少しずつ増大させる。便宜上、1日投与量全体を必要に応じて1日の間で何回かに分けて投与することができる。 For therapeutic use as antagonists of estrogen receptor signaling acting through inhibition of cell replication, the compounds utilized in the present invention are administered at an initial dosage of about 0.02 mg / kg to about 20 mg / kg daily. Administer. A daily dose range of about 0.05 mg / kg to about 2 mg / kg is preferred, and a daily dose range of about 0.05 mg / kg to about 1 mg / kg is most preferred. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound utilized. Determining the appropriate dose for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the entire daily dose can be administered in several portions during the day as needed.
塩/エステル
本発明に有用な組成物内の化合物又は本発明に有用な化合物は、塩又はエステル、特に薬学的に許容可能な塩又はエステルとして存在し得る。本発明の化合物の薬学的に許容可能な塩としては、好適な酸付加塩又はその塩基性塩が挙げられる。好適な薬学的な塩のレビュー(review)は、Berge et al, J Pharm Sci, 66,1-19(1977)に見ることができる。塩は、例えば鉱酸等の無機強酸、例えば硫酸、リン酸若しくはハロゲン化水素酸によって;有機強カルボン酸、例えば置換されていない若しくは(例えばハロゲンにより)置換された、1個〜4個の炭素原子を有するアルカンカルボン酸、例えば酢酸によって;飽和若しくは不飽和のジカルボン酸、例えばシュウ酸、マロン酸、コハク酸、マレイン酸、フマル酸、フタル酸若しくはテトラフタル酸によって;ヒドロキシカルボン酸、例えばアスコルビン酸、グリコール酸、乳酸、リンゴ酸、酒石酸若しくはクエン酸によって;アミノ酸、例えばアスパラギン酸若しくはグルタミン酸によって;安息香酸によって;又は有機スルホン酸、例えば置換されていない若しくは(例えばハロゲンにより)置換された、(C1〜C4)−アルキル−スルホン酸若しくはアリール−スルホン酸、例えばメタン−スルホン酸若しくはp−トルエンスルホン酸によって形成される。
Salt / Ester A compound within a composition useful in the present invention or a compound useful in the present invention may be present as a salt or ester, particularly a pharmaceutically acceptable salt or ester. Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition salts or basic salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are, for example, 1 to 4 carbons, which are strong inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acid; strong organic carboxylic acids, for example unsubstituted or substituted (for example by halogen) By an alkanecarboxylic acid having an atom, for example acetic acid; by a saturated or unsaturated dicarboxylic acid, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; a hydroxycarboxylic acid, for example ascorbic acid, Glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids such as unsubstituted or substituted (for example by halogen), (C 1 ~C 4) - alkyl - scan Formed with sulfonic acid or aryl-sulfonic acid, such as methane-sulfonic acid or p-toluenesulfonic acid.
エステルは、エステル化される官能基に応じて有機酸又はアルコール/水酸化物を用いて形成される。有機酸としては、カルボン酸、例えば置換されていない若しくは(例えばハロゲンにより)置換された、1個〜12個の炭素原子を有するアルカンカルボン酸、例えば酢酸;飽和若しくは不飽和のジカルボン酸、例えばシュウ酸、マロン酸、コハク酸、マレイン酸、フマル酸、フタル酸若しくはテトラフタル酸;ヒドロキシカルボン酸、例えばアスコルビン酸、グリコール酸、乳酸、リンゴ酸、酒石酸若しくはクエン酸;アミノ酸、例えばアスパラギン酸若しくはグルタミン酸;安息香酸;又は有機スルホン酸、例えば置換されていない若しくは(例えばハロゲンにより)置換された、(C1〜C4)−アルキル−スルホン酸若しくはアリール−スルホン酸、例えばメタン−スルホン酸若しくはp−トルエンスルホン酸が挙げられる。好適な水酸化物としては、無機水酸化物、例えば水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化アルミニウムが挙げられる。アルコールとしては、置換されていなくてもよく若しくは(例えばハロゲンにより)置換されていてもよい、1個〜12個の炭素原子を有するアルカンアルコールが挙げられる。 Esters are formed using organic acids or alcohols / hydroxides depending on the functional group being esterified. Organic acids include carboxylic acids such as alkane carboxylic acids having 1 to 12 carbon atoms, eg unsubstituted or substituted (eg by halogen), eg acetic acid; saturated or unsaturated dicarboxylic acids such as sulphur. Acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acid such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acid such as aspartic acid or glutamic acid; acid; or organic sulfonic acids, for example, are unsubstituted or (for example by halogen) substituted, (C 1 -C 4) - alkyl - sulfonic acid or aryl - sulfonic acid such as methanesulfonic - sulfonic acid or p- toluenesulfonic Examples include acids. Suitable hydroxides include inorganic hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide. Alcohols include alkane alcohols having 1 to 12 carbon atoms that may be unsubstituted or substituted (eg, with halogen).
同位体
本発明の化合物は、このような化合物を構成する1つ又は複数の原子に関する、非天然の割合の原子同位体を含有してもよい。本発明の作用因子又はその薬学的に許容可能な塩の変動同位体(isotopic variation)は、少なくとも1つの原子が、同じ原子番号を有するが通常自然に見られる原子質量と異なる原子質量を有する原子に置き換わったものと規定される。該作用因子及びその薬学的に許容可能な塩に組み込むことができる同位体の例としては、水素、炭素、窒素、酸素、リン、硫黄、フッ素及び塩素の同位体、例えばそれぞれ2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F及び36Clが挙げられる。該作用因子及びその薬学的に許容可能な塩の或る特定の変動同位体、例えば、放射性同位体、例えば3H又は14Cが組み込まれたものが、薬剤及び/又は基質の組織分布研究に有用である。トリチウム化した、すなわち3Hの、及び炭素−14、すなわち14Cの同位体がその調製のしやすさ及び検出能から特に好ましい。さらに、同位体、例えばデュートリウム、すなわち3Hによる置換は、代謝安定性の増大に起因する或る特定の治療的利点、例えばin vivo半減期の増大、又は投薬要件の低減をもたらすことができ、そのため或る環境下で好まれ得る。本発明の作用因子及び本発明のその薬学的に許容可能な塩の変動同位体は一般的に、好適な試薬の適切な変動同位体を用いて、従来の手順により調製することができる。
Isotopes The compounds of the present invention may contain unnatural proportions of atomic isotopes with respect to one or more of the atoms that constitute such compounds. An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is an atom in which at least one atom has the same atomic number but a different atomic mass than is normally found in nature. It is specified that it has been replaced with. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, eg, 2 H, 3 H, respectively. , 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Certain variable isotopes of the agent and its pharmaceutically acceptable salts, for example, those incorporating a radioactive isotope, such as 3 H or 14 C, are useful for drug and / or substrate tissue distribution studies. Useful. Tritiated, ie, 3 H, and carbon-14, ie, 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with isotopes such as deuterium, i.e. 3 H, can result in certain therapeutic benefits resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosing requirements. Therefore, it may be preferred under certain circumstances. The variable isotopes of the agents of the invention and pharmaceutically acceptable salts thereof of the invention can generally be prepared by conventional procedures, using the appropriate variable isotopes of suitable reagents.
本発明の化合物及び組成物の変動同位体は全て、放射性を有するか否かにかかわらず、本発明の範囲内に包含されることが意図される。 All isotopes of the compounds and compositions of the invention are intended to be included within the scope of the invention, whether radioactive or not.
溶媒和物
本発明は、本発明に有用な一般式(I)〜一般式(III)のいずれかによる組成物又は化合物の中に化合物の溶媒和物形態も含む。特許請求の範囲で使用されるこの用語はこれらの形態を包含する。
Solvates The present invention also includes solvate forms of the compounds within the compositions or compounds according to any of the general formulas (I)-(III) useful in the present invention. The terms used in the claims encompass these forms.
多形(Polymorphs)
本発明はさらに、様々な結晶形態、多形形態及び水和(又は無水)形態の、本発明に有用な本発明の組成物内の化合物又は式(I)による化合物に関する。化学的な化合物を、このような化合物の合成的な調製に用いられる溶媒からの(form)精製及び/又は単離方法をわずかに変更することによりこのような形態のいずれかで単離することができることが製薬業界内で十分に確立されている。
Polymorphs
The invention further relates to the compounds within the compositions of the invention useful according to the invention or compounds according to formula (I) in various crystalline, polymorphic and hydrated (or anhydrous) forms. Isolating a chemical compound in any such form by slightly modifying the form purification and / or isolation methods from the solvents used in the synthetic preparation of such compounds. Is well established within the pharmaceutical industry.
投与
本発明による化合物を、経口投与、直腸投与、胃内投与、頭蓋内投与、並びに非経口投与、例えば静脈内投与、筋肉内投与、鼻腔内投与、皮内投与、皮下投与及び同様の投与の経路を含む様々な既知の経路により投与することができる。非経口投与及び特定の静脈内投与(好ましくはデポー注射による)が好ましい。投与経路に応じて、種々の薬学的配合物が要求され、それらの中でも幾つかは、例えば消化管における本発明の化合物の分解を防止するために薬剤配合物に保護コーティングを塗布することを要求し得る。
Administration of the compounds according to the invention for oral administration, rectal administration, intragastric administration, intracranial administration and parenteral administration, for example intravenous administration, intramuscular administration, intranasal administration, intradermal administration, subcutaneous administration and similar administration Administration can be by a variety of known routes, including routes. Parenteral administration and specific intravenous administration (preferably by depot injection) are preferred. Depending on the route of administration, various pharmaceutical formulations are required, some of which require applying a protective coating to the drug formulation, for example to prevent degradation of the compounds of the invention in the gastrointestinal tract. Can do.
したがって、好ましくは、本発明の化合物を、シロップ、注入溶液若しくは注射溶液、錠剤、カプセル、カプレット(capslet)、トローチ剤、リポソーム、坐剤、硬膏、絆創膏、遅延型カプセル、粉末又は遅延放出配合物として配合する。好ましくは希釈剤は水、緩衝液、緩衝塩溶液又は塩溶液であり、担体は好ましくはココアバター及びビテベソール(vitebesole)からなる群から選択される。 Thus, preferably, the compounds of the invention are formulated into syrups, infusion or injection solutions, tablets, capsules, capslets, troches, liposomes, suppositories, plasters, bandages, delayed capsules, powders or delayed release formulations. As a blend. Preferably the diluent is water, buffer, buffered salt solution or salt solution and the carrier is preferably selected from the group consisting of cocoa butter and vitebesole.
本発明の化合物の投与のための特定の好ましい医薬品形態は、注射使用に好適な形態であり、滅菌水溶液又は滅菌分散液、及び滅菌注射溶液又は滅菌注射分散液の即席調製のための滅菌粉末を含む。全ての場合において、最終的な溶液形態又は分散液形態は滅菌されており、かつ流体でなければいけない。典型的には、このような溶液又は分散液は、例えば水緩衝水溶液、例えば生体適合性緩衝液、エタノール、ポリオール、例えばグリセロール、プロピレングリコール、ポリエチレングリコール、その好適な混合物、界面活性剤又は植物油を含有する溶媒又は分散媒を含む。本発明の化合物は、特に非経口投与のためにリポソーム中に配合することもできる。リポソームにより、遊離型薬剤と比較した場合の循環中の半減期の増大、及び封止型薬剤の持続的なより多くの放出という利点がもたらされる。 Certain preferred pharmaceutical forms for administration of the compounds of the invention are those suitable for injectable use, including sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Including. In all cases, the final solution or dispersion form must be sterile and must be fluid. Typically, such solutions or dispersions comprise, for example, an aqueous buffer solution such as a biocompatible buffer, ethanol, a polyol such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. Contains the solvent or dispersion medium it contains. The compounds of the invention can also be formulated in liposomes, particularly for parenteral administration. Liposomes provide the advantage of increased circulating half-life when compared to free drug and sustained more release of sealed drug.
注入溶液又は注射溶液の滅菌は、抗細菌剤又は抗真菌剤、例えばパラベン、クロロブタノール、フェノール、ソルビン酸又はチメロサール(thimersal)のような保存料の添加を含むが、これらに限定されない当該技術分野で認識されるあらゆる技法により達成することができる。さらには、等張剤、例えば糖類又は塩類、特に塩化ナトリウムを注入溶液又は注射溶液に組み込むことができる。 Sterilization of infusion or injection solutions includes the addition of preservatives such as, but not limited to, antibacterial or antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, or thimersal. Can be achieved by any technique recognized in In addition, isotonic agents such as sugars or salts, particularly sodium chloride can be incorporated into infusion or injection solutions.
本発明の化合物を1つ又は幾つか含有する滅菌注射溶液の製造は、要求される量で各化合物を要求されるような上で列挙された様々な成分を有する適切な溶媒に組み込み、その後滅菌することにより達成される。滅菌粉末を得るために、上記溶液を必要に応じて真空乾燥又は凍結乾燥する。本発明の好ましい希釈剤は、水、生理学的な許容可能な緩衝液、生理学的な許容可能な緩衝塩溶液又は塩溶液である。好ましい担体はココアバター及びビテベソールである。既に上で言及された好ましい賦形剤の他に、以下の賦形剤も様々な医薬品形態の本発明の化合物と共に使用するために選択することができるが、これらに限定されない:
a)結合剤、例えばラクトース、マンニトール、結晶性ソルビトール、二塩基性リン酸塩、リン酸カルシウム、糖類、微結晶性セルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ポリビニルピロリドン等;
b)潤滑剤、例えばステアリン酸マグネシウム、タルク、ステアリン酸カルシウム、ステアリン酸亜鉛、ステアリン酸、硬化植物油、ロイシン、グリセリド及びステアリルフマル酸ナトリウム、
c)崩壊剤、例えばデンプン、クロスカルメロース(croscaramellose)、メチルセルロースナトリウム、アガー、ベントナイト、アルギン酸、カルボキシメチルセルロース、ポリビニルピロリドン等。
The manufacture of sterile injectable solutions containing one or several compounds of the invention is the incorporation of each compound in the required amount into the appropriate solvent having the various ingredients listed above as required, followed by sterilization. Is achieved. To obtain a sterilized powder, the solution is vacuum-dried or freeze-dried as necessary. Preferred diluents of the present invention are water, physiologically acceptable buffer, physiologically acceptable buffered salt solution or salt solution. Preferred carriers are cocoa butter and vitebesol. In addition to the preferred excipients already mentioned above, the following excipients can also be selected for use with various pharmaceutical forms of the compounds of the invention, but are not limited to these:
a) Binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphate, calcium phosphate, saccharides, microcrystalline cellulose, carboxymethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone and the like;
b) Lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerides and sodium stearyl fumarate,
c) Disintegrants such as starch, croscaramellose, sodium methylcellulose, agar, bentonite, alginic acid, carboxymethylcellulose, polyvinylpyrrolidone and the like.
他の好適な賦形剤は、American Pharmaceutical Associationにより刊行された医薬賦形剤のハンドブック(参照により本明細書に援用される)に見ることができる。 Other suitable excipients can be found in the Pharmaceutical Excipient Handbook published by the American Pharmaceutical Association, which is incorporated herein by reference.
障害の重症度、及び本発明の化合物のうちの1つで治療可能な特定のタイプに、並びに治療される各患者、例えば患者の一般的健康状態等に応じて、治療効果又は予防効果を誘発するために異なる用量の各化合物が要求されることが理解されるものとする。適切な用量の決定は担当医師の裁量の範囲内である。本発明の治療的使用又は予防的使用における本発明の化合物の平均1日投与量は約0.1mg〜約3gの範囲内であることを考慮する。しかしながら、本発明の好ましい使用において、本発明の化合物を、1.0mg〜1000mgの範囲、好ましくは10mg〜500mgの範囲、好ましくは50mg〜200mgの範囲の量、それを必要とする被験体に投与する。本発明の化合物による治療期間及び投与頻度は、治療される疾患の重症度、並びに各々の個々の患者の病態及び特異的な(idiosyncratic)応答に応じて変わる。 Induces a therapeutic or prophylactic effect depending on the severity of the disorder and the particular type treatable with one of the compounds of the present invention, as well as each patient being treated, such as the general health of the patient It should be understood that different doses of each compound are required to do so. Determination of the appropriate dose is within the discretion of the attending physician. It is contemplated that the average daily dosage of the compounds of the present invention in therapeutic or prophylactic use of the present invention is in the range of about 0.1 mg to about 3 g. However, in a preferred use of the invention, a compound of the invention is administered to a subject in need thereof in an amount in the range of 1.0 mg to 1000 mg, preferably in the range of 10 mg to 500 mg, preferably in the range of 50 mg to 200 mg. To do. The duration of treatment and frequency of administration with the compounds of the invention will vary depending on the severity of the disease being treated, as well as the pathology and idiosyncratic response of each individual patient.
当該技術分野で知られるように、所定の組成物の薬学的に効果的な量は投与経路によっても変わる。概して、要求される量は、投与が胃腸管を介する;例えば坐剤による、直腸を介する、又は胃内プローブによるものである場合、より大きく、投与経路が非経口、例えば静脈内である場合、より小さい。典型的には、本発明の化合物は、直腸投与又は胃内投与が用いられる場合、50mg〜3g、好ましくは50mg〜500mgの範囲で、非経口投与が用いられる場合、10mg〜500mgの範囲で、投与する。 As is known in the art, the pharmaceutically effective amount of a given composition will also depend on the route of administration. In general, the amount required will be greater if administration is via the gastrointestinal tract; for example, via suppositories, via the rectum, or via an intragastric probe, and if the route of administration is parenteral, such as intravenously, Smaller than. Typically, the compounds of the invention will be in the range 50 mg to 3 g, preferably 50 mg to 500 mg when rectal or intragastric administration is used, and in the range 10 mg to 500 mg when parenteral administration is used. Administer.
本発明の化合物により治療可能な障害を発症するリスクを有することが知られている場合、本発明による医薬組成物の予防的投与が可能であり得る。これらの場合において、本発明の化合物をそれぞれ、好ましくは、上で概説した1日当たりの好ましい用量及び特に好ましい用量で投与する。この投与は各障害を発症するリスクが軽減するまで継続することができる。しかしながらほとんどの場合、本発明の化合物を疾患/障害が診断された時点で投与する。これらの場合では、第1の用量の本発明の化合物を1日に1回、2回、3回又は4回投与することが好ましい。好ましくは投与を1日間、1週間又は1ヶ月間中断し、それから各疾患の症状が悪化しなくなるか、又は改善するまで繰り返す。 Where it is known that there is a risk of developing a disorder treatable by a compound of the present invention, it may be possible to prevent the pharmaceutical composition according to the present invention from being administered. In these cases, each of the compounds of the present invention is preferably administered at a preferred daily dose and a particularly preferred dose as outlined above. This administration can be continued until the risk of developing each disorder has been reduced. In most cases, however, the compounds of the invention are administered when the disease / disorder is diagnosed. In these cases, it is preferred to administer the first dose of a compound of the invention once, twice, three times or four times a day. Preferably, dosing is interrupted for 1 day, 1 week or 1 month and then repeated until symptoms of each disease do not worsen or improve.
本発明の意義の範囲内で、置換基又は変数の組合せは、このような組合せが安定した又は化学的に実現可能な化合物をもたらす場合にのみ許容される。安定した化合物又は化学的に実現可能な化合物は、水分又は他の化学的に反応性の高い条件の非存在下で少なくとも1週間40℃以下の温度に維持した場合に実質的に変化しない化合物である。本発明は本明細書で開示される化合物の任意の塩基性の窒素含有基の四級化も想定している。水溶性若しくは油溶性、又は水分散性若しくは油分散性の生成物をこのような四級化により得ることができる。 Within the meaning of the invention, combinations of substituents or variables are permissible only if such combinations result in stable or chemically feasible compounds. A stable or chemically feasible compound is a compound that does not substantially change when maintained at a temperature of 40 ° C. or lower for at least one week in the absence of moisture or other chemically reactive conditions. is there. The present invention also contemplates quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water or oil-soluble or water-dispersible or oil-dispersible products can be obtained by such quaternization.
本発明の様々な変更形態及び変形形態が、本発明の範囲を逸脱することなく当業者にとって明らかであろう。本発明を特定の好ましい実施形態との関連で説明しているが、特許請求される本発明はこのような特定の実施形態に過度に限定されないとすることを理解されたい。実際、関連分野の当業者にとって明らかである、本発明を実施するために記載された形態の様々な変更形態が、本発明に含まれることが意図される。 Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it is to be understood that the claimed invention is not unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be included in the present invention.
以下の実施例及び図面は本発明の単なる例示にすぎず、添付の特許請求の範囲により示されるような本発明の範囲を限定するものとしては決して解釈すべきではない。 The following examples and drawings are merely illustrative of the invention and should in no way be construed as limiting the scope of the invention as indicated by the appended claims.
実験部
実施例で使用される全ての出発物質は市販されているか、又は有機化学の訓練を受けた平均的な当業者により、例えば実施例1で概説されるような日常的な研究作業により不当な負担なく合成され得る。
Experimental Section All starting materials used in the examples are either commercially available or are unwarranted by an average person skilled in organic chemistry, for example by routine research work as outlined in Example 1. Can be synthesized without undue burden.
実施例1で与えられる指針の他に、式I〜式IIIの化合物の合成に、及び式I〜式IIIの化合物の合成に関与する中間体の合成に利用することができる代替的な合成的変換が、当業者にとって既知であるか、又は当業者が容易に知ることができる。合成的変換のコレクションは、資料、例えばJ. March. Advanced Organic Chemistry, 4th ed.;John Wiley : New York(1992) R. C. Larock. Comprehensive OrganicTransformations, 2nd ed.;Wiley-VCH : New York(1999);F. A. Carey;R. J. Sundberg. Advanced OrganicChemistry, 2nd ed.;Plenum Press : New York(1984) T. W.Greene;P. G. M. Wuts. Protective Groups in OrganicSynthesis, 3rd ed.;John Wiley : New York(1999). L. S.Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2nded.;University Science Books: Mill Valley, CA(1994) L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis ;John Wiley : New York(1994). A. R. Katritzky;O. Meth-Cohn;C. W. Rees, Eds. ComprehensiveOrganic Functional Group Transformations;Pergamon Press: Oxford, UK(1995). G. Wilkinson;F. G A. Stone;E. W. Abel, Eds. Comprehensive Organometallic Chemistry;Pergamon Press : Oxford, UK(1982). B. M.Trost;I. Fleming. Comprehensive Organic Synthesis;Pergamon Press : Oxford, UK(1991) A. R. Katritzky;C. W. Rees Eds. Comprehensive Heterocylic Chemistry;Pergamon Press : Oxford, UK(1984) A. R.Katritzky;C. W. Rees;E. F. V.Scriven, Eds. Comprehensive Heterocylic Chemistry;PergamonPress : Oxford, UK(1996). C. Hansch;P. G. Sammes;J. B. Taylor, Eds.Comprehensive Medicinal Chemistry : Pergamon Press: Oxford, UK(1990)に見ることができる。 In addition to the guidance given in Example 1, alternative synthetic methods that can be used in the synthesis of compounds of formula I-III and in the synthesis of intermediates involved in the synthesis of compounds of formula I-III. The transformation is known to those skilled in the art or can be easily known by those skilled in the art. A collection of synthetic transformations can be found in materials such as J. March. Advanced Organic Chemistry, 4th ed .; John Wiley: New York (1992) RC Larock. Comprehensive Organic Transformations, 2nd ed .; Wiley-VCH: New York (1999); RJ Sundberg. Advanced Organic Chemistry, 2nd ed .; Plenum Press: New York (1984) TWGreene; PGM Wuts. Protective Groups in Organic Synthesis, 3rd ed .; John Wiley: New York (1999). LSHegedus. Transition Metals University Science Books: Mill Valley, CA (1994) LA Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994). AR Katritzky; O. Meth in the Synthesis of Complex Organic Molecules, 2nded. -Cohn; CW Rees, Eds. Comprehensive Organic Functional Group Transformations; Pergamon Press: Oxford, UK (1995). G. Wilkinson; F. G A. Stone; EW Abel, Eds. Comprehensive Organometallic Chemistry; Pergamon Press: Oxford, UK ( 1982). BMTrost; I. Fleming. Comprehensive Organic Synthesis; Pergam on Press: Oxford, UK (1991) AR Katritzky; CW Rees Eds. Comprehensive Heterocylic Chemistry; Pergamon Press: Oxford, UK (1984) ARKatritzky; CW Rees; EFVScriven, Eds. Comprehensive Heterocylic Chemistry; PergamonPress: Oxford, UK ( 1996). C. Hansch; PG Sammes; JB Taylor, Eds. Comprehensive Medicinal Chemistry: Pergamon Press: Oxford, UK (1990).
加えて、合成方法論及び関連のトピックのレビューの繰り返し(recurring)としては、Organic Reactions;John Wiley : New York;Organic Syntheses;John Wiley : New York;Reagents for OrganicSynthesis : John Wiley : New York;The Total Synthesisof Natural Products;John Wiley : New York;The Organic Chemistry of Drug Synthesis;JohnWiley : New York;Annual Reports in Organic Synthesis;Academic Press : San Diego CA;及びMethoden derOrganischen Chemie(Houben-Weyl);Thieme : Stuttgart, Germanyが挙げられる。さらに、合成的変換のデータベースとしては、CAS OnLine又はSciFinderのいずれかを用いて検索することができるChemical Abstracts、SpotFireを用いて検索することができるHandbuch der Organischen Chemie(Beilstein)、及びREACCSが挙げられる。 In addition, recurring synthesis methodologies and related topic reviews include: Organic Reactions; John Wiley: New York; Organic Syntheses; John Wiley: New York; Reagents for Organic Synthesis: John Wiley: New York; Natural Products; John Wiley: New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York; Annual Reports in Organic Synthesis; Academic Press: San Diego CA; and Methoden derOrganischen Chemie (Houben-Weyl); Can be mentioned. In addition, synthetic transformation databases include Chemical Abstracts that can be searched using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), and REACCS that can be searched using SpotFire. .
本明細書の化合物は、ISIS/Draw Add−Inに関するAutoNom Standardソフトウェアを用いて、IUPAC規格(standard)に従って命名した。 The compounds herein were named according to the IUPAC standard using AutoNom Standard software for ISIS / Draw Add-In.
実施例1:本発明の化合物の合成
本発明による一般式(I)〜一般式(III)の化合物を例えば以下のスキームに従って調製することができる:
Example 1 Synthesis of Compounds of the Invention Compounds of general formula (I) to general formula (III) according to the invention can be prepared, for example, according to the following scheme:
式中、R1〜R5は特許請求の範囲において規定されるようなものであるか、又は本明細書で規定のような特に好ましい意味を有し、RxはH及び/又はピナコラトである。 In which R 1 to R 5 are as defined in the claims or have a particularly preferred meaning as defined herein, and Rx is H and / or pinacolato.
上に示された一般的な反応スキームは以下の通りである: The general reaction scheme shown above is as follows:
一般的手順A。1:1(v/v)のトルエン/MeOH中に誘導体1(1.0当量)、Pd(dppf)Cl2・CH2Cl2(0.1当量)及び対応するヘテロ芳香族又は芳香族のボロン酸又はボロン酸エステル(1.2当量)の入ったフラスコを激しく攪拌しながらN2でパージし、2.0MのK2CO3水溶液(2.5当量)をゆっくりと添加した。混合物を90℃で4時間加熱した。冷却後、混合物をフラッシュカラムクロマトグラフィ(シリカゲル、EtOAc/ヘプタン、1:5から1:3へ)により精製し、誘導体2を得た(収率43%〜68%)。 General procedure A. Derivative 1 (1.0 eq), Pd (dppf) Cl 2 .CH 2 Cl 2 (0.1 eq) and the corresponding heteroaromatic or aromatic in 1: 1 (v / v) toluene / MeOH A flask containing boronic acid or boronic ester (1.2 eq) was purged with N 2 with vigorous stirring and 2.0 M aqueous K 2 CO 3 (2.5 eq) was added slowly. The mixture was heated at 90 ° C. for 4 hours. After cooling, the mixture was purified by flash column chromatography (silica gel, EtOAc / heptane, 1: 5 to 1: 3) to give derivative 2 (43% -68% yield).
一般的手順B。CH2Cl2中にアニリン誘導体1又はアニリン誘導体2(1.0当量)、対応する塩化スルホニル(1.1当量)及びピリジン(10当量)の入ったフラスコを室温で12時間攪拌した。混合物を濃NH4Cl水溶液で抽出し、ブラインで洗浄し、MgSO4で乾燥させた。有機溶媒を蒸発させ、粗生成物を分取HPLCにより又はフラッシュカラムクロマトグラフィ(シリカゲル、EtOAc/ヘプタン)により精製し、誘導体3又は誘導体4を得た(70%〜定量的な収率)。 General procedure B. A flask containing aniline derivative 1 or aniline derivative 2 (1.0 eq), the corresponding sulfonyl chloride (1.1 eq) and pyridine (10 eq) in CH 2 Cl 2 was stirred at room temperature for 12 hours. The mixture was extracted with concentrated aqueous NH 4 Cl, washed with brine and dried over MgSO 4 . The organic solvent was evaporated and the crude product was purified by preparative HPLC or by flash column chromatography (silica gel, EtOAc / heptane) to give derivative 3 or derivative 4 (70% to quantitative yield).
一般的手順C。乾燥MeOH中に誘導体4(1.0当量)、Pd(dppf)Cl2・CH2Cl2(0.1当量)及び対応するヘテロ芳香族又は芳香族のボロン酸又はボロン酸エステル(1当量)の入った2ml〜5ml容のマイクロ波反応容器を激しく攪拌しながらN2でパージし、2.0MのK2CO3水溶液(2.5当量)をゆっくりと添加した。容器に封をし、混合物をマイクロ波オーブンで90℃で30分間加熱した(CEM Discover Microwave system、Pmax=150Wに設定した)。冷却後、混合物をCH2Cl2で希釈し、セライトに通して濾過して、CH2Cl2で溶出した。有機溶媒を蒸発させ、粗生成物を分取HPLCにより又はフラッシュカラムクロマトグラフィ(シリカゲル、EtOAc/ヘプタン)により精製し、誘導体3を得た(収率42%〜90%)。 General procedure C. Derivative 4 (1.0 eq), Pd (dppf) Cl 2 .CH 2 Cl 2 (0.1 eq) and the corresponding heteroaromatic or aromatic boronic acid or boronic acid ester (1 eq) in dry MeOH A 2-5 ml microwave reaction vessel containing was purged with N 2 with vigorous stirring and 2.0 M aqueous K 2 CO 3 (2.5 eq) was slowly added. The vessel was sealed and the mixture was heated in a microwave oven at 90 ° C. for 30 minutes (CEM Discover Microwave system, P max = 150 W set). After cooling, the mixture was diluted with CH 2 Cl 2 , filtered through celite and eluted with CH 2 Cl 2 . The organic solvent was evaporated and the crude product was purified by preparative HPLC or by flash column chromatography (silica gel, EtOAc / heptane) to give derivative 3 (yield 42% -90%).
一般的手順D。アプローチ2は、示されるような追加の工程を任意に含んでいてもよい。ビスピナコラトジボロン(2.5当量)、Pd(dppf)Cl2・CH2Cl2(0.1当量)及びKOAc(3.0当量)を脱気した1,4−ジオキサン中に化合物4(1.0当量)を含有するフラスコに添加した。反応混合物を95℃に加熱し、4時間攪拌した。完了後、反応混合物をEtOAc(50ml)で希釈し、シリカゲルの短いカラムに通して濾過して、EtOAcでさらに溶出した。組み合わせた有機溶媒をH2O及びブラインで洗浄し、無水MgSO4で乾燥させ、真空濃縮した。得られた残渣をフラッシュカラムクロマトグラフィ(シリカゲル、EtOAc/ヘプタン、1:3)により精製し、クリーム又は白色固体としてボロン酸エステル5を得た(収率50%〜88%)。その後の工程で、化合物5をヘテロ芳香族又は芳香族の臭化物で変換し、手順A又は手順Cの後に誘導体3を得た。 General procedure D. Approach 2 may optionally include additional steps as shown. Compound 4 in 1,4-dioxane degassed bispinacolatodiboron (2.5 eq), Pd (dppf) Cl 2 .CH 2 Cl 2 (0.1 eq) and KOAc (3.0 eq) To a flask containing (1.0 eq). The reaction mixture was heated to 95 ° C. and stirred for 4 hours. After completion, the reaction mixture was diluted with EtOAc (50 ml), filtered through a short column of silica gel and further eluted with EtOAc. The combined organic solvent was washed with H 2 O and brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, EtOAc / heptane, 1: 3) to give boronate ester 5 as a cream or white solid (yield 50% -88%). In a subsequent step, compound 5 was converted with a heteroaromatic or aromatic bromide to give derivative 3 after Procedure A or Procedure C.
置換基R1及び/又はR4(アプローチ1又はアプローチ2に従い合成を行った場合、不要な反応を受ける可能性がある)を、アプローチ1又はアプローチ2による反応時には切断されないが既知の条件下で切断可能である従来の保護基により保護することができる。当業者は有機合成に利用することができる様々な保護基を知っている。保護基は例えば、Wuts, P.G.M. and Greene, T.W., Protective Groups in Organic Chemistry,3rd Ed., 1999;Wily & Sons Inc. and inKocienski, P.J., Protecting groups; 2nd Ed., 2000, Thieme MedicalPublishingにレビューされている。保護基は、保護される官能基に関して及び各保護基を選択的に除去する条件に関して、これらの参考文献で体系付けられている。使用することができる特に好ましい保護基は以下の通りである:
(i)酸性条件で、好ましくは4〜6のpHで除去される保護基(Boc又はトリチル保護基からなる群から選択される);
(ii)求核試薬により除去される保護基(Fmoc又はDde保護基からなる群から選択される);
(iii)水素化分解により除去される保護基(アリル型、tert−ブチル型、ベンジル型又はDmab(4−{N−[1−(4,4−ジメチル−2,6−ジオキソシクロヘキシリデン)−3−メチルブチル]アミノ}ベンジルエステル)からなる);
(iv)放射線により除去される保護基(ニトロベラトリルオキシカルボニル、ニトロベンジルオキシカルボニル、ジメチルジメトキシベンジルオキシカルボニル、5−ブロモ−7−ニトロインドリニル、o−ヒドロキシ−α−メチルシンナモイル及び2−オキシメチレンアントラキノンからなる群から選択される)。
Substituents R 1 and / or R 4 (which may undergo unwanted reactions when synthesized according to Approach 1 or Approach 2) are not cleaved during the reaction according to Approach 1 or Approach 2, but under known conditions It can be protected by conventional protecting groups that are cleavable. Those skilled in the art are aware of various protecting groups that can be utilized in organic synthesis. Protecting groups are reviewed in, for example, Wuts, PGM and Greene, TW, Protective Groups in Organic Chemistry, 3 rd Ed., 1999; Wily & Sons Inc. and in Kocienski, PJ, Protecting groups; 2 nd Ed., 2000, Thieme Medical Publishing Has been. Protecting groups are organized in these references with respect to the functional groups to be protected and with respect to conditions that selectively remove each protecting group. Particularly preferred protecting groups that can be used are as follows:
(I) a protecting group (selected from the group consisting of Boc or trityl protecting groups) which is removed under acidic conditions, preferably at a pH of 4-6;
(Ii) protecting groups removed by nucleophiles (selected from the group consisting of Fmoc or Dde protecting groups);
(Iii) Protecting groups removed by hydrogenolysis (allyl-type, tert-butyl-type, benzyl-type or Dmab (4- {N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene ) -3-methylbutyl] amino} benzyl ester));
(Iv) protecting groups removed by radiation (nitroveratryloxycarbonyl, nitrobenzyloxycarbonyl, dimethyldimethoxybenzyloxycarbonyl, 5-bromo-7-nitroindolinyl, o-hydroxy-α-methylcinnamoyl and 2- Selected from the group consisting of oxymethylene anthraquinone).
構成要素の合成
トルイジン構成要素(1)は、市販されているが、上で引用された文献に記載され、有機合成分野の通常の技術を有する者(当業者)に通常既知である標準的な官能化プロトコル又は変換プロトコルに従って合成することもできる。
Component Synthesis Toluidine component (1) is commercially available but is described in the literature cited above and is a standard known to those having ordinary skill in the field of organic synthesis (one skilled in the art). It can also be synthesized according to a functionalization protocol or a conversion protocol.
パラジウムで触媒されるカップリング反応に関する手順A及び手順Cに有用な多くの芳香族又はヘテロ芳香族のボロン酸又はボロン酸エステルは、市販されているか、又は上で引用された文献に記載され、有機合成分野の通常の技術を有する者(当業者)に通常既知である標準的な官能化プロトコル若しくは変換プロトコルに従って合成することができる。特に、このようなボロン酸/ボロン酸エステル中間体を、手順Dに例示されるように例えばそれらの対応する芳香族又はヘテロ芳香族のハロゲン化物前駆体から生成することができる。 Many aromatic or heteroaromatic boronic acids or boronic esters useful for Procedure A and Procedure C for palladium catalyzed coupling reactions are either commercially available or described in the literature cited above, They can be synthesized according to standard functionalization protocols or transformation protocols that are usually known to those having ordinary skill in the organic synthesis art (one skilled in the art). In particular, such boronic acid / boronic ester intermediates can be generated, for example, from their corresponding aromatic or heteroaromatic halide precursors as illustrated in Procedure D.
手順Bで使用され、そこではスルホニルクロリドで例示されたような多くの5員及び6員のヘテロ芳香族スルホン酸及びそれらの対応する活性化誘導体は、市販されているか、又は上で引用された文献に記載され、有機合成分野の通常の技術を有する者(当業者)に通常既知である標準的な官能化プロトコル若しくは変換プロトコルに従って合成することができる(具体的な方法が、例えば以下で説明されている:Caldwell, WT et al., J. Med. Chem.(1962), Vol.6,, p.58 ff;Caldwell, WT et al., JACS(1959), Vol.81, p.5166 ff;Roblin, RO et al., JACS(1950), Vol.72, p.4890 ff;Hitoshi K et al.、米国特許第5,811,571号(1998);国際公開第2006/090244号、p.38 ff;Janosik T et al., THL(2006), Vol.62,p.1699 ff;Allred GD, SERMACS(2007), Lanny LiebeskindCope Scholar Award Symposium II, 222. Sulfonyl Fluorides;及びその中で引用される参考文献)。必要に応じて、対応するチオールから直接、スルホンアミド3及び/又はスルホンアミド4を生成することも可能である(Wright SW et al., JOC(2006), Vol.71, p.1080 ff)。 Many 5- and 6-membered heteroaromatic sulfonic acids and their corresponding activated derivatives used in Procedure B, as exemplified by sulfonyl chloride, are either commercially available or cited above. It can be synthesized according to standard functionalization or transformation protocols described in the literature and commonly known to those having ordinary skill in the field of organic synthesis (one skilled in the art) (specific methods are described, for example, below) Caldwell, WT et al., J. Med. Chem. (1962), Vol. 6, p. 58 ff; Caldwell, WT et al., JACS (1959), Vol. 81, p. 5166 Roblin, RO et al., JACS (1950), Vol. 72, p. 4890 ff; Hitoshi K et al., US Pat. No. 5,811,571 (1998); WO 2006/090244; p.38 ff; Janosik T et al., THL (2006), Vol.62, p.1699 ff; Allred GD, SERMACS (2007), Lanny LiebeskindCope Scholar Award Symposium II, 222. Sulfonyl Fluo rides; and references cited therein). If necessary, sulfonamide 3 and / or sulfonamide 4 can be produced directly from the corresponding thiol (Wright SW et al., JOC (2006), Vol. 71, p. 1080 ff).
実施例2:本発明の化合物のHPLC/MS分析
化合物を以下の通り分析した:
最初の99:1から9.10分かけて1:99へと、その後1.80分間保持した線形勾配(水:アセトニトリル、調整剤(modifier)として0.2%ギ酸)によって、1.75ml/分の流速でWatersのX−bridge C18−カラム(粒径5μm、4.6×150mm(直径×長さ)を用いてHPLC/MSにより測定した。質量シグナルをWatersの3100 Mass Detectorを用いて決定した。
Example 2: HPLC / MS analysis of compounds of the invention Compounds were analyzed as follows:
A linear gradient (water: acetonitrile, 0.2% formic acid as a modifier) maintained from 1.99: 1 to 9.99 over 9.10 minutes followed by 1.80 minutes. Measured by HPLC / MS using a Waters X-bridge C18 -column (particle size 5 μm, 4.6 × 150 mm (diameter × length) at a flow rate of minutes. Mass signals were measured using a Waters 3100 Mass Detector. Were determined.
実施例3:一般的な細胞培養物の維持及び細胞増殖アッセイ
MCF−7ヒト乳腺癌細胞をATCC(LGC Promochem)から入手した。CellSensor(登録商標)HRE−bla HCT116細胞株(結腸直腸癌)をInvitrogenから入手した。
Example 3: General Cell Culture Maintenance and Cell Proliferation Assay MCF-7 human breast adenocarcinoma cells were obtained from ATCC (LGC Promochem). The CellSensor® HRE-bla HCT116 cell line (colorectal cancer) was obtained from Invitrogen.
細胞を、10%のウシ胎児血清(FBS)、100U/mlのペニシリン及び100μg/mlのストレプトマイシン、2mMのL−グルタミン、並びに選択マーカーとして5μg/mlのブラストサイジン(HRE−bla HCT116細胞株のみに対して)を添加したダルベッコ変法イーグル培地(DMEM:MCF−7)又はマッコイ5A培地(HRE−bla HCT116)中、加湿(95%)空気、5% CO2下37℃で成長させた。 Cells were treated with 10% fetal bovine serum (FBS), 100 U / ml penicillin and 100 μg / ml streptomycin, 2 mM L-glutamine, and 5 μg / ml blasticidin as a selectable marker (HRE-bla HCT116 cell line only) In Dulbecco's modified Eagle's medium (DMEM: MCF-7) or McCoy's 5A medium (HRE-bla HCT116) supplemented with (in contrast)) at 37 ° C. under humidified (95%) air, 5% CO 2 .
100μlの関連培地中に1ウェル当たり2000個の細胞で播種して、細胞増殖実験を96ウェル組織培養プレートにおいて行った。その後細胞を、化合物を添加する前に24時間、言及した条件下でインキュベートした。 Cell growth experiments were performed in 96-well tissue culture plates, seeded at 2000 cells per well in 100 μl of relevant media. Cells were then incubated under the conditions mentioned for 24 hours prior to compound addition.
細胞増殖の阻害の程度を決定するために、細胞を製造業者の取扱説明書に従ってATPlite溶液で処理し(PerkinElmer、ATPlite 1−step Luminescence ATP Detection Assay System)、ルシフェラーゼ表示値を、確立されたプロトコルに従い発光モードのEnvision HTSマルチラベルプレートリーダー(PerkinElmer)により測定した。生データをActivityBaseデータベース(IDBS,ID Business Solutions)にインポートし、EC50値をIDBSのプログラムActivityBase XEを用いて算出した。表2は、本発明の例示的な化合物に対して上で概説した細胞増殖アッセイで得られたIC50値を示す。細胞増殖アッセイデータは、本発明の化合物ががん細胞株における細胞増殖を阻害することができることを示す。 To determine the degree of inhibition of cell growth, cells are treated with ATPlite solution (PerkinElmer, ATPlite 1-step Luminescence ATP Detection Assay System) according to the manufacturer's instructions, and luciferase readings are determined according to established protocols. Measurements were made with an Envision HTS multilabel plate reader (PerkinElmer) in emission mode. Raw data was imported into ActivityBase database (IDBS, ID Business Solutions) and EC 50 values were calculated using the IDBS program ActivityBase XE. Table 2 shows the IC 50 values obtained in the cell proliferation assay outlined above for exemplary compounds of the invention. Cell proliferation assay data indicates that the compounds of the present invention can inhibit cell proliferation in cancer cell lines.
参照:EC50<500nM: +++
500nM〜1000nM:++
1μM〜10μM: +
Reference: EC 50 <500 nM: +++
500 nM to 1000 nM: ++
1 μM to 10 μM: +
「*」を付した保持時間は、実施例2で与えられたものの代替的な方法を用いて測定した。これらの保持時間を以下の通りに決定した:
最初の99:1から9.10分かけて1:99へと、その後1.80分保持した線形勾配(水:メタノール、調整剤として0.2%ギ酸)によって、1.75ml/分の流速でWatersのX−bridge C18−カラム(粒径5μm、4.6×150mm(直径×長さ)を用いてHPLC/MSにより測定した。質量シグナルをWatersの3100 Mass Detectorを用いて決定した。
Retention times marked with “*” were measured using an alternative method to that given in Example 2. These retention times were determined as follows:
A flow rate of 1.75 ml / min with a linear gradient (water: methanol, 0.2% formic acid as regulator) held from the first 99: 1 to 1:99 over 9.10 minutes and then 1.80 minutes Measured by HPLC / MS using a Waters X-bridge C18 -column (particle size 5 μm, 4.6 × 150 mm (diameter × length). Mass signals were determined using a Waters 3100 Mass Detector.
実施例4:in vitroでのチューブリン重合の阻害
in vitroでのチューブリン重合の阻害の程度を評価するために、チューブリン溶液(重合/脱重合のサイクルを伴う標準的な手順を用いてブタ脳から自家(in-house)調製した(Castoldi & Popov(2003)Protein Expr. Purif. 32(1):83-88を参照されたい)を重合条件下で様々な濃度の化合物と共にインキュベートし、90分の期間にわたり生じる重合の量(340nmでのOD変化により測定されるような)を決定するために、反応速度実験を行なった。
Example 4: Inhibition of tubulin polymerization in vitro To assess the extent of inhibition of tubulin polymerization in vitro, tubulin solution (a standard procedure with a polymerization / depolymerization cycle was used to prepare pigs. In-house prepared from the brain (see Castoldi & Popov (2003) Protein Expr. Purif. 32 (1): 83-88) was incubated with various concentrations of compound under polymerization conditions, 90 A kinetic experiment was performed to determine the amount of polymerization that occurred over a period of minutes (as measured by the OD change at 340 nm).
化合物溶液を再蒸留水で希釈し、5% DMSOを含有する10×溶液を最終的に得た。それから5μlの溶液を、チューブリンの添加に備えて384ウェルの底が透明な(clear-bottom)プレート(Corning番号3711、Corning Inc.)上のウェルに添加した。チューブリン溶液(80mMのK−PIPES[pH6.8](1mMのMgCl2、1mMのEGTA)中、19.6mg/ml)を4mg/mlの最終濃度まで氷冷G−PEM緩衝液(80mMのPIPES[pH6.8]、2mMのMgCl2、0.5mMのEGTA、10%グリセロール、1mMのGTP)で再懸濁し、少なくとも1分間氷上で維持した。それから50μlを予め分注した化合物溶液に添加し、プレートを5秒に設定して(setting for 5s)培地においてオービタルシェイカーにより振盪して(orbitalshaken)、直ちに第1の測定を開始した。 The compound solution was diluted with double-distilled water to finally obtain a 10 × solution containing 5% DMSO. 5 μl of the solution was then added to the wells on a 384 well clear-bottom plate (Corning No. 3711, Corning Inc.) in preparation for the addition of tubulin. Tubulin solution (19.6 mg / ml in 80 mM K-PIPES [pH 6.8] (1 mM MgCl 2 , 1 mM EGTA) in ice-cold G-PEM buffer (80 mM) to a final concentration of 4 mg / ml. PIPES [pH6.8], MgCl 2 of 2 mM, 0.5 mM of EGTA, 10% glycerol, resuspended in 1mM of GTP), and kept on ice for at least 1 minute. Then 50 μl was added to the pre-dispensed compound solution, the plate was set to 5 seconds (setting for 5s) and shaken with an orbital shaker in the medium and the first measurement started immediately.
実験を37℃の安定した温度に予め設定したSafire2(商標)モノクロメーター(Tecan)で行い、重合の程度を90分のサイクルにわたって1分毎に340nmでの溶液の吸光度を測定することにより決定した。報告された阻害値は90分での最終的な吸光度に基づいており、この試料で得られた最小シグナル及び最大シグナルを用いて、ビヒクル対照(0.5% DMSO)を参照して算出した。 The experiment was performed on a Safire 2 ™ monochromator (Tecan) preset to a stable temperature of 37 ° C. and the extent of polymerization was determined by measuring the absorbance of the solution at 340 nm every minute over a 90 minute cycle. did. The reported inhibition values are based on the final absorbance at 90 minutes and were calculated with reference to the vehicle control (0.5% DMSO) using the minimum and maximum signals obtained with this sample.
これらの実験により実証されるように(表2を参照されたい)、様々な実施例の構造特性の変化により、細胞増殖を阻害する上で活性を有し、HIF−シグナル伝達に影響を与えるが、チューブリン阻害特性を、標的となる生成物プロファイルにおいて望まれるか否かに応じて有する又は有しない化合物の選択を導くことができる。 As demonstrated by these experiments (see Table 2), changes in the structural properties of the various examples have activity in inhibiting cell proliferation and affect HIF-signaling. The selection of compounds with or without tubulin inhibitory properties depending on whether or not they are desired in the targeted product profile can be guided.
参照:10μMでの阻害>50%: +
20%〜50%:+/−
<20%: −
See: Inhibition at 10 μM> 50%: +
20% to 50%: +/-
<20%: −
実施例5:低酸素条件下でのHIFに媒介される転写の活性化の阻害
化合物処理による化学的に誘導された低酸素条件下での活性化したHIFシグナル伝達応答の阻害を、製造業者の取扱説明書に従ってInvitrogenのCellSensor(登録商標)HRE−bla HCT−116の安定してトランスフェクトしたレポーター細胞株を用いて決定した。HIFは、構成的に発現したHIF1βサブユニットと3つのHIFαサブユニット(HIF1α、HIF2α、HIF3α)のうちの1つとからなる転写因子である。このアッセイは、概してHIFα活性に対して応答性である。一例では、HIF−1は低酸素条件により安定化される場合、幾つかの遺伝子を上方調節し、低酸素条件下での細胞生存を促進する。これらには、酸素非依存的なATP合成を可能とする解糖酵素、及び血管形成を促進する血管内皮成長因子(VEGF)が含まれる。HIF−1は、配列NCGTGを一般的に含有するプロモーターにおいてHIF応答要素(HRE)と結合することにより作用する。
Example 5: Inhibition of HIF-mediated transcriptional activation under hypoxic conditions Inhibition of activated HIF signaling responses under chemically-induced hypoxic conditions by compound treatment Determined using a stably transfected reporter cell line of Invitrogen's CellSensor® HRE-bla HCT-116 according to instructions. HIF is a transcription factor consisting of a constitutively expressed HIF1β subunit and one of three HIFα subunits (HIF1α, HIF2α, HIF3α). This assay is generally responsive to HIFα activity. In one example, when HIF-1 is stabilized by hypoxic conditions, it upregulates several genes and promotes cell survival under hypoxic conditions. These include glycolytic enzymes that allow oxygen-independent ATP synthesis and vascular endothelial growth factor (VEGF) that promotes angiogenesis. HIF-1 acts by binding to a HIF response element (HRE) in a promoter that generally contains the sequence NCGTG.
細胞を先に記載のように維持し、32μlのアッセイ培地(Opti−MEM[Invitrogen]、0.5% FBS、100U/mlのペニシリン、100μg/mlのストレプトマイシン、0.1mMの非必須アミノ酸[NEAA]、1mMのピルビン酸ナトリウム、5mMのHEPES[pH7.3])中で1ウェル当たり15000個の細胞で384ウェルの底が透明なプレート(Corning 3712)に播種した。2時間のインキュベーション期間後、続いて化合物(4μl)を5% DMSO中で10×濃度で細胞に添加し、30分間通常の条件下でインキュベートした。低酸素条件を誘導するために、2mMのデフェロキサミン(DFO)溶液4μlを細胞に添加し、その後標準的なアッセイ条件下で24時間インキュベートした(記載のように)。対照ウェルは、培地だけしか含有しないウェル(細胞なし)、及び化合物の代わりに0.5% DMSOで処理したウェルを含んでいた。 Cells were maintained as previously described and 32 μl assay medium (Opti-MEM [Invitrogen], 0.5% FBS, 100 U / ml penicillin, 100 μg / ml streptomycin, 0.1 mM non-essential amino acids [NEAA ] 15,000 cells per well in 1 mM sodium pyruvate, 5 mM HEPES [pH 7.3]), seeded in 384 well bottom clear plates (Corning 3712). After a 2 hour incubation period, compound (4 μl) was subsequently added to the cells at 10 × concentration in 5% DMSO and incubated for 30 minutes under normal conditions. To induce hypoxic conditions, 4 μl of 2 mM deferoxamine (DFO) solution was added to the cells and then incubated for 24 hours under standard assay conditions (as described). Control wells included wells containing only medium (no cells) and wells treated with 0.5% DMSO instead of compound.
読み出しの前に、基質負荷溶液(Substrate Loading Solution)を製造業者のプロトコルに記載のように調製し、その10μlをそれぞれのウェルに添加した。室温及び暗所でのさらに2時間のインキュベーション後、蛍光をPerkinElmerのEnvision HTSにより2つの波長(青色チャネル:ex.409nm、em.460nm、緑色チャネル:ex.409nm、em.530nm)で測定した。分析のために、青色チャネルデータ及び緑色チャネルデータそれぞれから460nm及び530nmでの細胞を含まないウェルの平均シグナルを初めに減算した。それから青色/緑色の発光比を、バックグラウンド補正した青色発光値をバックグラウンド補正した緑色発光値で除算することでそれぞれのウェルに関して算出した。IC50値を、GraphPad Prism(Prism 5、GraphPad software, Inc.)を用いてこれらの比から決定した。 Prior to reading, a Substrate Loading Solution was prepared as described in the manufacturer's protocol and 10 μl was added to each well. After an additional 2 hours incubation at room temperature and in the dark, fluorescence was measured by PerkinElmer Envision HTS at two wavelengths (blue channel: ex.409 nm, em.460 nm, green channel: ex.409 nm, em.530 nm). For analysis, the average signal of wells without cells at 460 nm and 530 nm was first subtracted from the blue and green channel data, respectively. The blue / green emission ratio was then calculated for each well by dividing the background corrected blue emission value by the background corrected green emission value. IC 50 values were determined from these ratios using GraphPad Prism (Prism 5, GraphPad software, Inc.).
これらの実験の結果(表2を参照されたい)は、本発明の化合物が、低酸素条件下で低酸素調節要素に媒介される転写活性を阻害することができることを示す。本発明の化合物は、従来技術で説明されるHIF−阻害剤化合物、例えば現在臨床試験を受けていることが報告されている唯一の小分子HIF−阻害剤であるProlX化合物PX−478等を超える効力レベルを有する。 The results of these experiments (see Table 2) show that the compounds of the invention can inhibit transcriptional activity mediated by hypoxia regulatory elements under hypoxic conditions. The compounds of the present invention exceed the HIF-inhibitor compounds described in the prior art, such as the ProlX compound PX-478, the only small molecule HIF-inhibitor currently reported to be undergoing clinical trials. Has potency level.
参照:EC50<500nM: +++
500nM〜1000nM:++
1μM〜10μM: +
Reference: EC 50 <500 nM: +++
500 nM to 1000 nM: ++
1 μM to 10 μM: +
実施例6:本発明によるさらなる有用な化合物
また表3で例示される化合物が、本発明の範囲内で特に有用である。これらの化合物は、実施例1で概説したように、また上で記載したように有機化学において既知である製造の実施により製造することができる。これらの化合物は、表2で列挙され実施例3〜実施例5で試験した化合物で示されたものと同程度の阻害活性を有する。
Example 6: Further useful compounds according to the invention The compounds exemplified in Table 3 are also particularly useful within the scope of the present invention. These compounds can be prepared as outlined in Example 1 and by manufacturing practices known in organic chemistry as described above. These compounds have inhibitory activity comparable to that shown for the compounds listed in Table 2 and tested in Examples 3-5.
考察
上で記載した実施例で示されたデータから直接的に、本発明の化合物がHIFの機能を阻害すると共に細胞増殖を阻害する共通の特性を有するということになる。したがって、これらの化合物は、炎症性疾患、過剰増殖性疾患又は過剰増殖性障害、低酸素関連病変、及び過剰な血管新生を特徴とする疾患からなる群から選択される疾患又は障害の治療又は予防のための治療用化合物として有用である。
DISCUSSION Directly from the data presented in the examples described above, it can be seen that the compounds of the present invention have the common property of inhibiting the function of HIF as well as inhibiting cell proliferation. Accordingly, these compounds treat or prevent a disease or disorder selected from the group consisting of inflammatory diseases, hyperproliferative diseases or hyperproliferative disorders, hypoxia-related lesions, and diseases characterized by excessive angiogenesis. Useful as a therapeutic compound for
全ての本発明の化合物が共有する上で記載した有用な特性に加えて、これらの化合物は、チューブリン組織化(organization)の阻害に関して種々の程度の効力も示す。このことは、患者の疾患状態、体質及び遺伝的素因に応じて患者ごとに選択的に投与することができる治療用化合物の提供にある本発明のさらに貴重な貢献を示す。これに関連して、チューブリン阻害剤としてさらなる活性を有する又は有しない本発明の化合物で患者を治療すべきか否かを決めることがさらに可能である。 In addition to the useful properties described above shared by all compounds of the present invention, these compounds also exhibit varying degrees of efficacy with respect to inhibition of tubulin organization. This represents a further valuable contribution of the present invention in providing therapeutic compounds that can be selectively administered per patient depending on the disease state, constitution and genetic predisposition of the patient. In this context, it is further possible to decide whether patients should be treated with the compounds of the invention with or without further activity as tubulin inhibitors.
Claims (19)
R1は、単環式の5員又は6員のヘテロアリールであり、H、アルキル、アルケニル、アルキニル、−CN、ハロゲン、N−O(該窒素原子は該単環式の5員又は6員のヘテロアリールの一体部分である)、−OH、アルコキシ、−SH、S−アルキル、−NH2、NH−アルキル、N−ビス−アルキル、NHOH、NMeOH、NMe(OMe)、−NO2、−CF3、−OCF3及びC1〜C4ヒドロキシアルキルからなる群から選択される1つ又は複数の置換基で任意に置換され、
R2はH又はC1〜C4アルキルであり、
R3はH又は−CH3であり、
R4は、フェニル、又は単環式の5員若しくは6員のヘテロアリールであり、アルキル、アルケニル、アルキニル、アルコキシ、ハロゲン、−CN、−CF3、−OCF3、C1〜C4ヒドロキシアルキル、−OH、−SH、S−アルキル、−CN、N−ビス−アルキル、シアノアセチレン、−NO2、−NR7R8、−C(O)R6、N−O(該窒素原子は該単環式の5員又は6員のヘテロアリールの一体部分である)、及び(R4がフェニルである場合)ジオキシメチレン架橋(−O−CH2−O−)を共に形成する2つの置換基からなる群から選択される1つ又は複数の置換基で任意に置換され、
R5はH又は−CH3であり、
R6はC1〜C4アルキルであり、
R7はH又はアルキルであり、
R8はH又はC1〜C4アルキルであり、
ただしR1は5−クロロ−チオフェン−2−イルではなく、R5及びR3は同時にHではない)
による構造を有する化合物。 Formula I:
R 1 is a monocyclic 5- or 6-membered heteroaryl, and H, alkyl, alkenyl, alkynyl, —CN, halogen, N—O (wherein the nitrogen atom is the monocyclic 5- or 6-membered) is an integral part of the heteroaryl), - OH, alkoxy, -SH, S- alkyl, -NH 2, NH- alkyl, N- bis - alkyl, NHOH, NMeOH, NMe (OMe ), - NO 2, - Optionally substituted with one or more substituents selected from the group consisting of CF 3 , —OCF 3 and C 1 -C 4 hydroxyalkyl,
R 2 is H or C 1 -C 4 alkyl;
R 3 is H or —CH 3 ;
R 4 is phenyl or monocyclic 5- or 6-membered heteroaryl, alkyl, alkenyl, alkynyl, alkoxy, halogen, —CN, —CF 3 , —OCF 3 , C 1 -C 4 hydroxyalkyl , —OH, —SH, S-alkyl, —CN, N-bis-alkyl, cyanoacetylene, —NO 2 , —NR 7 R 8 , —C (O) R 6 , N—O (the nitrogen atom is the Two substitutions that together form a dioxymethylene bridge (—O—CH 2 —O—) (when R 4 is phenyl), which is an integral part of a monocyclic 5- or 6-membered heteroaryl Optionally substituted with one or more substituents selected from the group consisting of groups,
R 5 is H or —CH 3 ;
R 6 is C 1 -C 4 alkyl;
R 7 is H or alkyl;
R 8 is H or C 1 -C 4 alkyl;
Where R 1 is not 5-chloro-thiophen-2-yl and R 5 and R 3 are not H at the same time)
A compound having a structure according to
R9及びR10は各々個々に、H、C1〜C4アルキル、C1〜C4アルケニル、C1〜C4アルキニル、−CN、−C(O)R6、シアノアセチレン、ハロゲン、−OH、C1〜C4アルコキシ、−SH、C1〜C4 S−アルキル、−NH2、C1〜C4 NH−アルキル、C1〜C4 N−ビス−アルキル、−NO2、−CF3、−OCF3及びC1〜C4ヒドロキシアルキルからなる群から選択され、又はR9及びR10は、ジオキシメチレン架橋(−O−CH2−O−)を共に形成し、
R11及びR12は各々個々に、H、C1〜C4アルキル、C1〜C4アルケニル、C1〜C4アルキニル、−CN、ハロゲン、−OH、C1〜C4アルコキシ、−SH、C1〜C4 S−アルキル、−CF3、−OCF3、−NH2、−N(CH3)2及びC1〜C4ヒドロキシアルキルからなる群から選択され、
ただしR9及びR12が同時にメトキシである場合はなく、
R6は上で示した意味を有し、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
による構造を有する、請求項1〜3のいずれか一項に記載の化合物。 R 4 is of formula IV:
R 9 and R 10 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, -CN, -C (O) R 6 , cyanoacetylene, halogen,- OH, C 1 ~C 4 alkoxy, -SH, C 1 ~C 4 S- alkyl, -NH 2, C 1 ~C 4 NH- alkyl, C 1 ~C 4 N- bis - alkyl, -NO 2, - Selected from the group consisting of CF 3 , —OCF 3 and C 1 -C 4 hydroxyalkyl, or R 9 and R 10 together form a dioxymethylene bridge (—O—CH 2 —O—);
R 11 and R 12 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, -CN, halogen, -OH, C 1 -C 4 alkoxy, -SH Selected from the group consisting of: C 1 -C 4 S-alkyl, —CF 3 , —OCF 3 , —NH 2 , —N (CH 3 ) 2 and C 1 -C 4 hydroxyalkyl;
However, R 9 and R 12 are not simultaneously methoxy,
R 6 has the meaning indicated above;
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
The compound according to any one of claims 1 to 3, which has a structure represented by:
R2がH、メチル又はエチルであり、
R5がHである、請求項5に記載の化合物。 R 3 is methyl;
R 2 is H, methyl or ethyl;
6. A compound according to claim 5, wherein R < 5 > is H.
A、B、D及びEは各々個々に、窒素原子、CR13及びN−Oからなる群から選択され、
Gは、酸素原子、硫黄原子及びNR14からなる群から選択され、
R13は、H、C1〜C3アルキル、C1〜C3アルコキシ、−OH、−SH、S−アルキル、−CF3、−OCF3、ハロゲン、−NR15R16、−NO2、−CN、−C(O)R6、アセチレン、シアノアセチレン、C1〜C4ヒドロキシアルキル、及びR4を式(I)〜式(III)のいずれかによる化合物と連結するσ(シグマ)結合からなる群から選択され、
R14は、H、C1〜C4アルキル、及びR4を式(I)〜式(III)のいずれかによる化合物と連結するσ(シグマ)結合からなる群から選択され、
R15及びR16は各々個々に、H又はC1〜C4アルキルであり、
R6は上で示した意味を有し、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
による構造を有する、請求項1〜3のいずれか一項に記載の化合物。 R 4 is of formula V:
A, B, D and E are each individually selected from the group consisting of a nitrogen atom, CR 13 and N—O;
G is selected from the group consisting of an oxygen atom, a sulfur atom and NR 14 ;
R 13 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —OH, —SH, S-alkyl, —CF 3 , —OCF 3 , halogen, —NR 15 R 16 , —NO 2 , Σ (Sigma) bond linking —CN, —C (O) R 6 , acetylene, cyanoacetylene, C 1 -C 4 hydroxyalkyl, and R 4 with a compound according to any of formulas (I) to (III) Selected from the group consisting of
R 14 is selected from the group consisting of H, C 1 -C 4 alkyl, and σ (sigma) bond linking R 4 with a compound according to any of formulas (I) to (III);
R 15 and R 16 are each independently H or C 1 -C 4 alkyl;
R 6 has the meaning indicated above;
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
The compound according to any one of claims 1 to 3, which has a structure represented by:
L及びTは各々個々に、CH基又は窒素原子又はN−Oであり、
M、N及びQは各々個々に、窒素原子、CR17基及びN−Oからなる群から選択され、
R17は、H、C1〜C3アルキル、C1〜C3アルコキシ、−CF3、−OCF3、ハロゲン、−OH、−NO2、−SH、C1〜C3 S−アルキル、−NR15R16、C1〜C4ヒドロキシアルキル、−C(O)R6、アセチレン、シアノアセチレン及び−CNからなる群から選択され、
R15及びR16は各々個々に、H又はC1〜C4アルキルであり、
R6は上で示した意味を有し、
*は、R4と式(I)〜式(III)のいずれかによる化合物との間の結合を示す)
による構造を有する、請求項1〜3のいずれか一項に記載の化合物。 R 4 is of formula VI:
L and T are each independently a CH group, a nitrogen atom or N—O,
M, N and Q are each independently selected from the group consisting of a nitrogen atom, a CR 17 group and N—O;
R 17 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —CF 3 , —OCF 3 , halogen, —OH, —NO 2 , —SH, C 1 to C 3 S-alkyl, — Selected from the group consisting of NR 15 R 16 , C 1 -C 4 hydroxyalkyl, —C (O) R 6 , acetylene, cyanoacetylene and —CN;
R 15 and R 16 are each independently H or C 1 -C 4 alkyl;
R 6 has the meaning indicated above;
* Indicates a bond between R 4 and a compound according to any of formulas (I) to (III))
The compound according to any one of claims 1 to 3, which has a structure represented by:
(式中、
R18及びR19は各々個々に、H、C1〜C3アルキル、C1〜C3アルコキシ、−CF3、−OCF3、ハロゲン、−OH、−NO2、−SH、C1〜C3 S−アルキル、−NR15R16、C1〜C4ヒドロキシアルキル、アルキニル、アルケニル、−C(O)R6、シアノアセチレン及び−CNからなる群から選択され、
R15、R16及びR6は、上で示した意味を有する)
からなる群から選択される、請求項1〜3のいずれか一項に記載の化合物。 R 4 is
(Where
R 18 and R 19 are each independently H, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, —CF 3 , —OCF 3 , halogen, —OH, —NO 2 , —SH, C 1 to C. Selected from the group consisting of 3 S-alkyl, —NR 15 R 16 , C 1 -C 4 hydroxyalkyl, alkynyl, alkenyl, —C (O) R 6 , cyanoacetylene and —CN;
R 15 , R 16 and R 6 have the meanings indicated above)
The compound according to any one of claims 1 to 3, which is selected from the group consisting of:
からなる任意に置換された単環式の5員のヘテロ芳香族残基の群から選択される、請求項1〜9のいずれか一項に記載の化合物。 R 2 is H and R 1 is
10. A compound according to any one of claims 1 to 9 selected from the group of optionally substituted monocyclic 5-membered heteroaromatic residues consisting of
からなる任意に置換された単環式の6員のヘテロ芳香族残基の群から選択される、請求項1〜9のいずれか一項に記載の化合物。 R 2 is H and R 1 is
10. A compound according to any one of claims 1 to 9 selected from the group of optionally substituted monocyclic 6-membered heteroaromatic residues consisting of
A method of treating a hyperproliferative disease or disorder, wherein the patient receives radiation therapy, chemotherapy, immunotherapy, laser / microwave hyperthermia, or gene therapy using antisense DNA and / or RNA Before, during and / or after receiving, administering to the patient a compound according to any one of claims 1 to 12, or a composition according to claim 14. Method.
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PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
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US20100029609A1 (en) * | 2006-09-08 | 2010-02-04 | Frederic Berst | Biaryl sulfonamide derivatives |
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2008
- 2008-12-30 WO PCT/EP2008/011148 patent/WO2010085968A1/en active Application Filing
-
2009
- 2009-12-30 US US13/142,518 patent/US20120095012A1/en not_active Abandoned
- 2009-12-30 JP JP2011543998A patent/JP2012514019A/en not_active Withdrawn
- 2009-12-30 WO PCT/EP2009/009338 patent/WO2010076034A1/en active Application Filing
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016508969A (en) * | 2012-12-14 | 2016-03-24 | フューシス セラピューティクス、インク. | Methods and compositions for inhibiting CNKSR1 |
Also Published As
Publication number | Publication date |
---|---|
WO2010076034A1 (en) | 2010-07-08 |
US20120095012A1 (en) | 2012-04-19 |
WO2010085968A1 (en) | 2010-08-05 |
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